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  • 1.
    Andrae, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Gouveia, Maria Leonor Seguardo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    PDGFR alpha signaling is required for alveolar development in the mouse lung2017In: Mechanisms of Development, ISSN 0925-4773, E-ISSN 1872-6356, Vol. 145, p. S147-S147Article in journal (Other academic)
  • 2.
    Andrae, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Ehrencrona, Hans
    Gallini, Radiosa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Lal, Mark
    Ding, Hao
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Analysis of Mice Lacking the Heparin-Binding Splice Isoform of Platelet-Derived Growth Factor A2013In: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 33, no 20, p. 4030-4040Article in journal (Refereed)
    Abstract [en]

    Platelet-derived growth factor A-chain (PDGF-A) exists in two evolutionarily conserved isoforms, PDGF-Along and PDGF-Ashort, generated by alternative RNA splicing. They differ by the presence (in PDGF-Along) or absence (in PDGF-Ashort) of a carboxyterminal heparin/heparan sulfate proteoglycan-binding motif. In mice, similar motifs present in other members of the PDGF and vascular endothelial growth factor (VEGF) families have been functionally analyzed in vivo, but the specific physiological importance of PDGF-A(long) has not been explored previously. Here, we analyzed the absolute and relative expression of the two PDGF-A splice isoforms during early postnatal organ development in the mouse and report on the generation of a Pdgfa allele (Pdgfa(Delta ex6) incapable of producing PDGF-A(long) due to a deletion of the exon 6 splice acceptor site. In situations of limiting PDGF-A signaling through PDGF receptor alpha (PDGFR alpha), or in mice lacking PDGF-C, homozygous carriers of Pdgfa(Delta ex6) showed abnormal development of the lung, intestine, and vertebral column, pinpointing developmental processes where PDGF-A(long) may play a physiological role.

  • 3.
    Andrae, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Gouveia, Leonor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Gallini, Radiosa
    Karolinska Inst, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden..
    He, Liqun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Fredriksson, Linda
    Karolinska Inst, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden..
    Nilsson, Ingrid
    Karolinska Inst, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden..
    Johansson, Bengt R.
    Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Electron Microscopy Unit, S-40530 Gothenburg, Sweden..
    Eriksson, Ulf
    Karolinska Inst, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    A role for PDGF-C/PDGFR alpha signaling in the formation of the meningeal basement membranes surrounding the cerebral cortex2016In: BIOLOGY OPEN, ISSN 2046-6390, Vol. 5, no 4, p. 461-474Article in journal (Refereed)
    Abstract [en]

    Platelet-derived growth factor-C (PDGF-C) is one of three known ligands for the tyrosine kinase receptor PDGFR alpha. Analysis of Pdgfc null mice has demonstrated roles for PDGF-C in palate closure and the formation of cerebral ventricles, but redundancy with other PDGFR alpha ligands might obscure additional functions. In search of further developmental roles for PDGF-C, we generated mice that were double mutants for Pdgfc(-/-) and Pdgfra(GFP/+). These mice display a range of severe phenotypes including spina bifida, lung emphysema, abnormal meninges and neuronal over-migration in the cerebral cortex. We focused our analysis on the central nervous system (CNS), where PDGF-C was identified as a critical factor for the formation of meninges and assembly of the glia limitans basement membrane. We also present expression data on Pdgfa, Pdgfc and Pdgfra in the cerebral cortex and microarray data on cerebral meninges.

  • 4.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, AZ ICMC, Huddinge, Sweden.
    Cell-cell signaling in blood vessel development and function2018In: EMBO Molecular Medicine, ISSN 1757-4676, E-ISSN 1757-4684, Vol. 10, no 3, article id UNSP e8610Article in journal (Other academic)
    Abstract [en]

    The blood vasculature is an organ pervading all other organs (almost). During vascular development, cell-cell signaling by extracellular ligands and cell surface receptors ensure that new vessels sprout into non-vascularized regions and simultaneously acquire organ-specific specializations and adaptations that match the local physiological needs. The vessels thereby specialize in their permeability, molecular transport between blood and tissue, and ability to regulate blood flow on demand. Over the past decades, we have learnt about the generic cell-cell signaling mechanisms governing angiogenic sprouting, mural cell recruitment, and vascular remodeling, and we have obtained the first insights into signals that induce and maintain vascular organotypicity. However, intra-organ vascular diversity and arterio-venous hierarchies complicate the molecular characterization of the vasculature's cellular building blocks. Single-cell RNA sequencing provides a way forward, as it allows elucidation at a genome-wide and quantitative level of the transcriptional diversity occurring within the same cell types at different anatomical positions and levels of arterio-venous hierarchy in the organs. In this Louis-Jeantet Prize Winner: Commentary, I give a brief overview of vascular development and how recent advances in the field pave the way for more systematic efforts to explore vascular functions in health and disease.

  • 5.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Institutionen för medicinsk biokemi och biofysik, Karolinska Institutet.
    Double function at the blood-brain barrier2014In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 509, no 7501, p. 432-433Article in journal (Other academic)
  • 6.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Lipid transport and human brain development2015In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 47, no 7, p. 699-701Article in journal (Other academic)
    Abstract [en]

    How the human brain rapidly builds up its lipid content during brain growth and maintains its lipids in adulthood has remained elusive. Two new studies show that inactivating mutations in MFSD2A, known to be expressed specifically at the blood-brain barrier, lead to microcephaly, thereby offering a simple and surprising solution to an old enigma.

  • 7.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Transcriptional control of endothelial energy2016In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 529, no 7585, p. 160-161Article in journal (Other academic)
  • 8.
    Betsholtz, Christer
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Keller, Annika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    PDGF, Pericytes and the Pathogenesis of Idiopathic Basal Ganglia Calcification (IBGC)2014In: Brain Pathology, ISSN 1015-6305, E-ISSN 1750-3639, Vol. 24, no 4, p. 387-395Article in journal (Refereed)
    Abstract [en]

    Platelet-derived growth factors (PDGFs) are important mitogens for various types of mesenchymal cells, and as such, they exert critical functions during organogenesis in mammalian embryonic and early postnatal development. Increased or ectopic PDGF activity may also cause or contribute to diseases such as cancer and tissue fibrosis. Until recently, no loss-of-function (LOF) mutations in PDGF or PDGF receptor genes were reported as causally linked to a human disease. This changed in 2013 when reports appeared on presumed LOF mutations in the genes encoding PDGF-B and its receptor PDGF receptor-beta (PDGF-R) in familial idiopathic basal ganglia calcification (IBGC), a brain disease characterized by anatomically localized calcifications in or near the blood microvessels. Here, we review PDGF-B and PDGF-R biology with special reference to their functions in brain-blood vessel development, pericyte recruitment and the regulation of the blood-brain barrier. We also discuss various scenarios for IBGC pathogenesis suggested by observations in patients and genetically engineered animal models of the disease.

  • 9.
    Castro, Marco
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Laviña, Bàrbara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Ando, Koji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Álvarez-Aznar, Alberto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Brakebusch, Cord
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. FOM, the FIRC Institute of Molecular Oncology, Milan, Italy.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. AstraZeneca/Karolinska Integrated Cardio Metabolic Centre (ICMC), Karolinska Institutet.
    Gängel, Konstantin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    CDC42 deletion elicits cerebral vascular malformations via increased MEKK3-dependent KLF4 expressionManuscript (preprint) (Other academic)
  • 10.
    De La Fuente, Alerie Guzman
    et al.
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England..
    Lange, Simona
    Paracelsus Med Univ Salzburg, Inst Mol Regenerat Med, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria..
    Silva, Maria Elena
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England.;Paracelsus Med Univ Salzburg, Inst Mol Regenerat Med, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Univ Austral Chile, Fac Med, Inst Anat Histol & Pathol, Lab Stem Cells & Neuroregenerat, Valdivia, Chile.;Univ Austral Chile, Ctr Interdisciplinary Studies Nervous Syst CISNe, Valdivia, Chile.;Univ Austral Chile, Inst Pharm, Fac Sci, Valdivia, Chile..
    Gonzalez, Ginez A.
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England..
    Tempfer, Herbert
    Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Inst Tendon & Bone Regenerat, A-5020 Salzburg, Austria.;Austrian Cluster Tissue Regenerat, Vienna, Austria..
    van Wijngaarden, Peter
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England.;Univ Melbourne, Dept Surg, Royal Victorian Eye & Ear Hosp, Ctr Eye Res Australia,Ophthalmol, Melbourne, Vic, Australia..
    Zhao, Chao
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England..
    Di Canio, Ludovica
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England..
    Trost, Andrea
    Paracelsus Med Univ Salzburg, Inst Mol Regenerat Med, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Ophthalmol Optometry & Res Program Expt Ophthalmo, A-5020 Salzburg, Austria..
    Bieler, Lara
    Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Inst Expt Neuroregenerat, A-5020 Salzburg, Austria..
    Zaunmair, Pia
    Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Inst Expt Neuroregenerat, A-5020 Salzburg, Austria..
    Rotheneichner, Peter
    Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Inst Expt Neuroregenerat, A-5020 Salzburg, Austria..
    O'Sullivan, Anna
    Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Inst Expt Neuroregenerat, A-5020 Salzburg, Austria..
    Couillard-Despres, Sebastien
    Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Inst Expt Neuroregenerat, A-5020 Salzburg, Austria..
    Errea, Oihana
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England..
    Mäe, Maarja A.
    Uppsala Univ, Rudbeck Lab, Dept Immunol Genet & Pathol, S-75185 Uppsala, Sweden..
    Andrae, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    He, Liqun
    Tianjin Med Univ, Key Lab Post Neuroinjury Neuro Repair & Regenerat, Tianjin Neurol Inst, Dept Neurosurg,Gen Hosp,Minist Educ & Tianjin Cit, Tianjin 300052, Peoples R China..
    Keller, Annika
    Zurich Univ, Zurich Univ Hosp, Div Neurosurg, CH-8091 Zurich, Switzerland..
    Batiz, Luis F.
    Univ Austral Chile, Fac Med, Inst Anat Histol & Pathol, Lab Stem Cells & Neuroregenerat, Valdivia, Chile.;Univ Los Andes, Fac Med, CIB, Santiago, Chile..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Aigner, Ludwig
    Paracelsus Med Univ Salzburg, Inst Mol Regenerat Med, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Austrian Cluster Tissue Regenerat, Vienna, Austria..
    Franklin, Robin J. M.
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England..
    Rivera, Francisco J.
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England.;Paracelsus Med Univ Salzburg, Inst Mol Regenerat Med, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Univ Austral Chile, Fac Med, Inst Anat Histol & Pathol, Lab Stem Cells & Neuroregenerat, Valdivia, Chile.;Univ Austral Chile, Ctr Interdisciplinary Studies Nervous Syst CISNe, Valdivia, Chile..
    Pericytes Stimulate Oligodendrocyte Progenitor Cell Differentiation during CNS Remyelination2017In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 20, no 8, p. 1755-1764Article in journal (Refereed)
    Abstract [en]

    The role of the neurovascular niche in CNS myelin regeneration is incompletely understood. Here, we show that, upon demyelination, CNS-resident pericytes (PCs) proliferate, and parenchymal non-vessel-associated PC-like cells (PLCs) rapidly develop. During remyelination, mature oligodendrocytes were found in close proximity to PCs. In Pdgfb(ret/ret) mice, which have reduced PC numbers, oligodendrocyte progenitor cell (OPC) differentiation was delayed, although remyelination proceeded to completion. PC-conditioned medium accelerated and enhanced OPC differentiation in vitro and increased the rate of remyelination in an ex vivo cerebellar slice model of demyelination. We identified Lama2 as a PC-derived factor that promotes OPC differentiation. Thus, the functional role of PCs is not restricted to vascular homeostasis but includes the modulation of adult CNS progenitor cells involved in regeneration.

  • 11.
    Dias, Mariana
    et al.
    Theodor Kocher Inst, Bern, Switzerland..
    Coisne, Caroline
    Theodor Kocher Inst, Bern, Switzerland..
    Baden, Pascale
    Theodor Kocher Inst, Bern, Switzerland..
    Lazarevic, Ivana
    Theodor Kocher Inst, Bern, Switzerland..
    Francisco, David
    Univ Bern, Bern, Switzerland..
    Lyck, Ruth
    Theodor Kocher Inst, Bern, Switzerland..
    Enzmann, Gaby
    Theodor Kocher Inst, Bern, Switzerland..
    Deutsch, Urban
    Theodor Kocher Inst, Bern, Switzerland..
    Bruggmann, Remy
    Univ Bern, Bern, Switzerland..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Uppsala, Sweden..
    Furuse, Mikio
    Natl Inst Physiol Sci, Okazaki, Aichi, Japan..
    Engelhardt, Britta
    Theodor Kocher Inst, Bern, Switzerland..
    Claudin 3-Deficient C57BL/6 Mice Display Intact Brain Barriers2017In: Journal of Vascular Research, ISSN 1018-1172, E-ISSN 1423-0135, Vol. 54, p. 63-63Article in journal (Other academic)
  • 12.
    Franzen, Oscar
    et al.
    Karolinska Inst, Integrated Cardio Metab Ctr, Huddinge, Sweden..
    Ermel, Raili
    Tartu Univ Hosp, Dept Cardiac Surg, Tartu, Estonia..
    Sukhavasi, Katyayani
    Univ Tartu, Inst Biomed & Translat Med, Dept Pathophysiol, Tartu, Estonia..
    Jain, Rajeev
    Univ Tartu, Inst Biomed & Translat Med, Dept Pathophysiol, Tartu, Estonia..
    Jain, Anamika
    Univ Tartu, Inst Biomed & Translat Med, Dept Pathophysiol, Tartu, Estonia..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Integrated Cardio Metab Ctr, Huddinge, Sweden.
    Giannarelli, Chiara
    Icahn Sch Med Mt Sinai, Cardiovasc Res Ctr, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, New York, NY 10029 USA..
    Kovacic, Jason C.
    Icahn Sch Med Mt Sinai, Cardiovasc Res Ctr, New York, NY 10029 USA..
    Ruusalepp, Arno
    Tartu Univ Hosp, Dept Cardiac Surg, Tartu, Estonia.;Univ Tartu, Inst Biomed & Translat Med, Dept Pathophysiol, Tartu, Estonia.;Clin Gene Networks AB, Stockholm, Sweden..
    Skogsberg, Josefin
    Karolinska Inst, Dept Med Biochem & Biophys, Solna, Sweden..
    Hao, Ke
    Icahn Sch Med Mt Sinai, Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, New York, NY 10029 USA..
    Schadt, Eric E.
    Icahn Sch Med Mt Sinai, Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, New York, NY 10029 USA.;Clin Gene Networks AB, Stockholm, Sweden..
    Bjoerkegren, Johan L. M.
    Karolinska Inst, Integrated Cardio Metab Ctr, Huddinge, Sweden.;Univ Tartu, Inst Biomed & Translat Med, Dept Pathophysiol, Tartu, Estonia.;Icahn Sch Med Mt Sinai, Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, New York, NY 10029 USA.;Clin Gene Networks AB, Stockholm, Sweden..
    Global analysis of A-to-I RNA editing reveals association with common disease variants2018In: PeerJ, ISSN 2167-8359, E-ISSN 2167-8359, Vol. 6, article id e4466Article in journal (Refereed)
    Abstract [en]

    RNA editing modifies transcripts and may alter their regulation or function. In humans, the most common modification is adenosine to inosine (A-to-I). We examined the global characteristics of RNA editing in 4,301 human tissue samples. More than 1.6 million A-to-I edits were identified in 62% of all protein-coding transcripts. mRNA recoding was extremely rare; only 11 novel recoding sites were uncovered. Thirty single nucleotide polymorphisms from genome-wide association studies were associated with RNA editing; one that influences type 2 diabetes (rs2028299) was associated with editing in ARPIN. Twenty-five genes, including LRP11 and PLIN5, had editing sites that were associated with plasma lipid levels. Our findings provide new insights into the genetic regulation of RNA editing and establish a rich catalogue for further exploration of this process.

  • 13.
    Furuhashi, Masao
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Abramsson, Alexandra
    Ellingsen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Li, Hong
    Bergsten-Folestad, Erika
    Eriksson, Ulf
    Heuchel, Rainer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Östman, Arne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Platelet-derived growth factor production by B16 melanoma cells leads to increased pericyte abundance in tumors and an associated increase in tumor growth rate2004In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 64, no 8, p. 2725-2733Article in journal (Refereed)
    Abstract [en]

    Platelet-derived growth factor (PDGF) receptor signaling participates in different processes in solid tumors, including autocrine stimulation of tumor cell growth, recruitment of tumor stroma fibroblasts, and stimulation of tumor angiogenesis. In the present study, the B16 mouse melanoma tumor model was used to investigate the functional consequences of paracrine PDGF stimulation of host-derived cells. Production of PDGF-BB or PDGF-DD by tumor cells was associated with an increased tumor growth rate. Characterization of tumors revealed an increase in pericyte abundance in tumors derived from B16 cells producing PDGF-BB or PDGF-DD. The increased tumor growth rate associated with PDGF-DD production was not seen in mice expressing an attenuated PDGF beta-receptor and was thus dependent on host PDGF beta-receptor signaling. The increased pericyte abundance was not associated with an increased tumor vessel density. However, tumor cell apoptosis, but not proliferation, was reduced in tumors displaying PDGF-induced increased pericyte coverage. Our findings thus demonstrate that paracrine PDGF production stimulates pericyte recruitment to tumor vessels and suggest that pericyte abundance influences tumor cell apoptosis and tumor growth.

  • 14.
    Gallini, Radiosa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden..
    Huusko, Jenni
    Univ Kuopio, Dept Biotechnol & Mol Med, Al Virtanen Inst Mol Sci, Kuopio, Finland..
    Yla-Herttuala, Seppo
    Univ Kuopio, Dept Biotechnol & Mol Med, Al Virtanen Inst Mol Sci, Kuopio, Finland..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden..
    Andrae, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Isoform-Specific Modulation of Inflammation Induced by Adenoviral Mediated Delivery of Platelet-Derived Growth Factors in the Adult Mouse Heart2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 8, article id e0160930Article in journal (Refereed)
    Abstract [en]

    Platelet-derived growth factors (PDGFs) are key regulators of mesenchymal cells in vertebrate development. To what extent PDGFs also exert beneficial homeostatic or reparative roles in adult organs, as opposed to adverse fibrogenic responses in pathology, are unclear. PDGF signaling plays critical roles during heart development, during which forced overexpression of PDGFs induces detrimental cardiac fibrosis; other studies have implicated PDGF signaling in post-infarct myocardial repair. Different PDGFs may exert different effects mediated through the two PDGF receptors (PDGFR alpha and PDGFR beta) in different cell types. Here, we assessed responses induced by five known PDGF isoforms in the adult mouse heart in the context of adenovirus vector-mediated inflammation. Our results show that different PDGFs have different, in some cases even opposing, effects. Strikingly, whereas the major PDGFRa agonists (PDGF-A and -C) decreased the amount of scar tissue and increased the numbers of PDGFR alpha-positive fibroblasts, PDGFR beta agonists either induced large scars with extensive inflammation (PDGF-B) or dampened the adenovirusinduced inflammation and produced a small and dense scar (PDGF-D). These results provide evidence for PDGF isoform-specific inflammation-modulating functions that may have therapeutic implications. They also illustrate a surprising complexity in the PDGF-mediated pathophysiological responses.

  • 15.
    Gallini, Radiosa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden..
    Lindblom, Per
    Gothenburg Univ, Sahlgrenska Acad, Dept Med Biochem, Gothenburg, Sweden.;AstraZeneca R&D, Molndal, Sweden..
    Bondjers, Cecilia
    Gothenburg Univ, Sahlgrenska Acad, Dept Med Biochem, Gothenburg, Sweden.;Sahlgrens Univ Hosp, Gothenburg, Sweden..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden..
    Andrae, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    PDGF-A and PDGF-B induces cardiac fibrosis in transgenic mice2016In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 349, no 2, p. 282-290Article in journal (Refereed)
    Abstract [en]

    Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) contribute to normal heart development. Deficient or abnormal expression of Pdgf and Pdgfr genes have a negative impact on cardiac development and function. The cellular effects of PDGFs in the hearts of Pdgf/Pdgfr mutants and the pathogenesis of the resulting abnormalities are poorly understood, but different PDGF isoforms induce varying effects. Here, we generated three new transgenic mouse types which complete a set of studies, where all different PDGF ligands have been expressed under the same heart specific alpha-myosin heavy chain promoter. Transgenic expression of the natural isoforms of Pdgfa and Pdgfb resulted in isoform specific fibrotic reactions and cardiac hypertrophy. Pdgfa overexpression resulted in a severe fibrotic reaction with up to 8-fold increase in cardiac size, leading to lethal cardiac failure within a few weeks after birth. In contrast, Pdgfb overexpression led to focal fibrosis and moderate cardiac hypertrophy. As PDGF-A and PDGF-B have different affinity for the two PDGF receptors, we analyzed the expression of the receptors and the histology of the fibrotic hearts. Our data suggest that the stronger fibrotic effect generated by Pdgfa overexpression was mediated by Pdgfra in cardiac interstitial mesenchymal cells, i.e. the likely source of extracellular matrix depostion and fibrotic reaction. The apparent sensitivity of the heart to ectopic PDGFR alpha agonists supports a role for endogenous PDGFRa agonists in the pathogenesis of cardiac fibrosis.

  • 16.
    Gladh, Hanna
    et al.
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden..
    Folestad, Erika Bergsten
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden..
    Muhl, Lars
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden..
    Ehnman, Monika
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden.;Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Tannenberg, Philip
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden.;Karolinska Univ Hosp, Div Vasc Surg, Dept Surg Sci, Stockholm, Sweden..
    Lawrence, Anna-Lisa
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden.;Univ Michigan, Sch Med, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI USA..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden..
    Eriksson, Ulf
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden..
    Mice Lacking Platelet-Derived Growth Factor D Display a Mild Vascular Phenotype2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 3, article id e0152276Article in journal (Refereed)
    Abstract [en]

    Platelet-derived growth factor D (PDGF-D) is the most recently discovered member of the PDGF family. PDGF-D signals through PDGF receptor beta, but its biological role remains largely unknown. In contrast to other members of the PDGF family of growth factors, which have been extensively investigated using different knockout approaches in mice, PDGF-D has until now not been characterized by gene inactivation in mice. Here, we present the phenotype of a constitutive Pdgfd knockout mouse model (Pdgfd(-/-)), carrying a LacZ reporter used to visualize Pdgfd promoter activity. Inactivation of the Pdgfd gene resulted in a mild phenotype in C57BL/6 mice, and the offspring was viable, fertile and generally in good health. We show that Pdgfd reporter gene activity was consistently localized to vascular structures in both postnatal and adult tissues. The expression was predominantly arterial, often localizing to vascular bifurcations. Endothelial cells appeared to be the dominating source for Pdgfd, but reporter gene activity was occasionally also found in sub-populations of mural cells. Tissue-specific analyses of vascular structures revealed that NG2-expressing pericytes of the cardiac vasculature were disorganized in Pdgfd(-/-) mice. Furthermore, Pdgfd(-/-) mice also had a slightly elevated blood pressure. In summary, the vascular expression pattern together with morphological changes in NG2-expressing cells, and the increase in blood pressure, support a function for PDGF-D in regulating systemic arterial blood pressure, and suggests a role in maintaining vascular homeostasis.

  • 17.
    Gouveia, Leonor
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Integrated Cardio Metab Ctr, Huddinge, Sweden..
    Andrae, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Expression analysis of platelet-derived growth factor receptor alpha and its ligands in the developing mouse lung2017In: Physiological Reports, E-ISSN 2051-817X, Vol. 5, no 6, article id e13092Article in journal (Refereed)
    Abstract [en]

    Activation of the platelet-derived growth factor receptor-a (PDGFRa) signaling pathway is critically important during lung alveogenesis, the process in lung development during which alveoli are formed from the terminal alveolar sacs. Several studies have aimed to characterize the expression patterns of PDGFRa and its two ligands (PDGF-A and -C) in the lung, but published analyses have been limited to embryonic and/or perinatal time points, and no attempts have been made to characterize both receptor and ligand expression simultaneously. In this study, we present a detailed map of the expression patterns of PDGFRa, PDGF-A and PDGF-C during the entire period of lung development, that is, from early embryogenesis until adulthood. Three different reporter mice were analyzed (Pdgfa ex4-COIN-INV-lacZ, Pdgfc tm1Nagy, and Pdgfra tm11(EGFP) Sor), in which either lacZ or H2B-GFP were expressed under the respective promoter in gene-targeted alleles. A spatiotemporal dynamic expression was identified for both ligands and receptor. PDGF-A and PDGF-C were located to distinct populations of epithelial and smooth muscle cells, whereas PDGFRa expression was located to different mesenchymal cell populations. The detailed characterization of gene expression provides a comprehensive map of PDGFRa signaling in lung cells, opening up for a better understanding of the role of PDGF signaling during lung development.

  • 18.
    Gouveia, Leonor
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Andrae, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    PDGF-A signaling is required for secondary alveolar septation and controls epithelial proliferation in the developing lung2018In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 145, no 7, article id dev161976Article in journal (Refereed)
    Abstract [en]

    Platelet-derived growth factor A (PDGF-A) signaling through PDGF receptor a is essential for alveogenesis. Previous studies have shown that Pdgfa(-/-) mouse lungs have enlarged alveolar airspace with absence of secondary septation, both distinctive features of bronchopulmonary dysplasia. To study how PDGF-A signaling is involved in alveogenesis, we generated lung-specific Pdgfa knockout mice (Pdgfa(fl/-); Spc-cre) and characterized their phenotype postnatally. Histological differences between mutant mice and littermate controls were visible after the onset of alveogenesis and maintained until adulthood. Additionally, we generated Pdgfa(fl/-); Spc-cre; Pdgfra(GFP/+) mice in which Pdgfra(+) cells exhibit nuclear GFP expression. In the absence of PDGF-A, the number of Pdgfra(GFP+) cells was significantly decreased. In addition, proliferation of Pdgfra(GFP+) cells was reduced. During alveogenesis, Pdgfra(GFP+) myofibroblasts failed to form the alpha-smooth muscle actin rings necessary for alveolar secondary septation. These results indicate that PDGF-A signaling is involved in myofibroblast proliferation and migration. In addition, we show an increase in both the number and proliferation of alveolar type II cells in Pdgfa(fl/-); Spc-cre lungs, suggesting that the increased alveolar airspace is not caused solely by deficient myofibroblast function.

  • 19.
    Guzman, A.
    et al.
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge, England..
    Lange, S.
    Paracelsus Med Univ, Inst Mol Regenerat Med, Salzburg, Austria.;Spinal Cord Injury & Tissue Regenerat Ctr SCI TRe, Salzburg, Austria..
    Silva, M. E.
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge, England.;Paracelsus Med Univ, Inst Mol Regenerat Med, Salzburg, Austria.;Spinal Cord Injury & Tissue Regenerat Ctr SCI TRe, Salzburg, Austria.;Univ Austral Chile, Inst Pharm, Fac Sci, Valdivia, Chile.;Ctr Interdisciplinary Studies Nervous Syst CISNe, Valdivia, Chile..
    Gonzalez, G. A.
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge, England..
    Tempfer, H.
    Spinal Cord Injury & Tissue Regenerat Ctr SCI TRe, Salzburg, Austria.;Paracelsus Med Univ, Inst Tendon & Bone Regenerat, Salzburg, Austria.;Austrian Cluster Tissue Regenerat, Vienna, Austria..
    van Wijngaarden, P.
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge, England.;Royal Victorian Eye & Ear Hosp, Melbourne, Vic, Australia.;Univ Melbourne, Ctr Eye Res Australia, Melbourne, Vic, Australia.;Univ Melbourne, Ophthalmol, Dept Surg, Melbourne, Vic, Australia..
    Zhao, C.
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge, England..
    Rotheneichner, P.
    Paracelsus Med Univ, Inst Mol Regenerat Med, Salzburg, Austria.;Spinal Cord Injury & Tissue Regenerat Ctr SCI TRe, Salzburg, Austria.;Paracelsus Med Univ, Inst Expt Neuroregenerat, Salzburg, Austria..
    Trost, A.
    Paracelsus Med Univ, Inst Mol Regenerat Med, Salzburg, Austria.;Spinal Cord Injury & Tissue Regenerat Ctr SCI TRe, Salzburg, Austria.;Paracelsus Med Univ, Ophthalmol Optometry & Res Program Expt Ophthalmo, Salzburg, Austria..
    O'Sullivan, A.
    Spinal Cord Injury & Tissue Regenerat Ctr SCI TRe, Salzburg, Austria.;Paracelsus Med Univ, Inst Expt Neuroregenerat, Salzburg, Austria..
    Couillard-Despres, S.
    Spinal Cord Injury & Tissue Regenerat Ctr SCI TRe, Salzburg, Austria.;Paracelsus Med Univ, Inst Expt Neuroregenerat, Salzburg, Austria..
    Bieler, L.
    Spinal Cord Injury & Tissue Regenerat Ctr SCI TRe, Salzburg, Austria.;Paracelsus Med Univ, Inst Expt Neuroregenerat, Salzburg, Austria..
    Errea, O.
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge, England..
    Mae, Maarja Andaloussi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Andrae, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    He, Liqun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Keller, A.
    Zurich Univ, Zurich Univ Hosp, Div Neurosurg, Zurich, Switzerland..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Div Vasc Biol, Dept Med Biochem & Biophys, Stockholm, Sweden..
    Aigner, L.
    Paracelsus Med Univ, Inst Mol Regenerat Med, Salzburg, Austria.;Spinal Cord Injury & Tissue Regenerat Ctr SCI TRe, Salzburg, Austria..
    Franklin, R. J. M.
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge, England..
    Rivera, F. J.
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge, England.;Paracelsus Med Univ, Inst Mol Regenerat Med, Salzburg, Austria.;Spinal Cord Injury & Tissue Regenerat Ctr SCI TRe, Salzburg, Austria.;Univ Austral Chile, Inst Anat Histol & Pathol, Fac Med, Valdivia, Chile.;Ctr Interdisciplinary Studies Nervous Syst CISNe, Valdivia, Chile..
    Pericytes promote the generation of oligodendrocytes during remyelination2017In: Glia, ISSN 0894-1491, E-ISSN 1098-1136, Vol. 65, no S1, p. E541-E542Article in journal (Other academic)
  • 20.
    Gängel, Konstantin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Endocytosis regulates VEGF signalling during angiogenesis2013In: Nature Cell Biology, ISSN 1465-7392, E-ISSN 1476-4679, Vol. 15, no 3, p. 233-235Article in journal (Other academic)
    Abstract [en]

    Endocytosis has proved to be a versatile mechanism regulating diverse cellular processes, ranging from nutrient uptake to intracellular signal transduction. New work reinforces the importance of endocytosis for VEGF receptor signalling and angiogenesis in the developing eye, and describes a mechanism for its differential regulation in angiogenic versus quiescent endothelial cells.

  • 21. He, Bing
    et al.
    Ebarasi, Lwaki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Zhao, Zhe
    Guo, Jing
    Ojala, Juha R. M.
    Hultenby, Kjell
    De Val, Sarah
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Tryggvason, Karl
    Lmx1b and FoxC Combinatorially Regulate Podocin Expression in Podocytes2014In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 25, no 12, p. 2764-2777Article in journal (Refereed)
    Abstract [en]

    Podocin is a key protein of the kidney podocyte slit diaphragm protein complex, an important part of the glomerular filtration barrier. Mutations in the human podocin gene NPHS2 cause familial or sporadic forms of renal disease owing to the disruption of filtration barrier integrity. The exclusive expression of NPHS2 in podocytes reflects its unique function and raises interesting questions about its transcriptional regulation. Here, we further define a 2.5-kb zebrafish nphs2 promoter fragment previously described and identify a 49-bp podocyte-specific transcriptional enhancer using Tol2-mediated G(0) transgenesis in zebrafish. Within this enhancer, we identified a cis-acting element composed of two adjacent DNA-binding sites (FLAT-E and forkhead) bound by transcription factors Lnnx1b and FoxC. In zebrafish, double knockdown of Lmx1b and FoxC orthologs using morpholino doses that caused no or minimal phenotypic changes upon individual knockdown completely disrupted podocyte development in 40% of injected embryos. Co-overexpression of the two genes potently induced endogenous nphs2 expression in zebrafish podocytes. We found that the NPHS2 promoter also contains a cis-acting Lmx1b-FoxC motif that binds LMX1B and FoxC2. Furthermore, a genome-wide search identified several genes that carry the Lmx1b-FoxC motif in their promoter regions. Among these candidates, motif-driven podocyte enhancer activity of CCNC and MEIS2 was functionally analyzed in vivo. Our results show that podocyte expression of some genes is combinatorially regulated by two transcription factors interacting synergistically with a common enhancer. This finding provides insights into transcriptional mechanisms required for normal and pathologic podocyte functions.

  • 22.
    He, Liqun
    et al.
    Tianjin Med Univ Gen Hosp, Key Lab Postneuroinjury Neurorepair & Regenerat C, Minist Educ & Tianjin City, Dept Neurosurg,Tianjin Neurol Inst, Tianjin 300052, Peoples R China.
    Vanlandewijck, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Dept Med Huddinge, Integrated Cardio Metab Ctr, Blickagangen 6, SE-14157 Huddinge, Sweden.
    Mäe, Maarja Andaloussi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Andrae, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Ando, Koji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Del Gaudio, Francesca
    Karolinska Inst, Dept Cell & Mol Biol, Von Eulers Vag 3, SE-17177 Stockholm, Sweden.
    Nahar, Khayrun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Lebouvier, Thibaud
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Univ Lille, CHU, Memory Ctr, Inserm,U1171,Distalz, F-59000 Lille, France.
    Lavina, Barbara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Gouveia, Maria Leonor Seguardo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Sun, Ying
    Zhongyuan Union Genet Technol Co Ltd, Dept Bioinformat, 45 9th East Rd, Tianjin 300304, Peoples R China.
    Raschperger, Elisabeth
    Karolinska Inst, Dept Med Huddinge, Integrated Cardio Metab Ctr, Blickagangen 6, SE-14157 Huddinge, Sweden.
    Segerstolpe, Asa
    Karolinska Inst, Dept Med Huddinge, Integrated Cardio Metab Ctr, Blickagangen 6, SE-14157 Huddinge, Sweden.
    Liu, Jianping
    Karolinska Inst, Dept Med Huddinge, Integrated Cardio Metab Ctr, Blickagangen 6, SE-14157 Huddinge, Sweden.
    Gustafsson, Sonja
    Karolinska Inst, Dept Med Huddinge, Integrated Cardio Metab Ctr, Blickagangen 6, SE-14157 Huddinge, Sweden.
    Rasanen, Markus
    Univ Helsinki, Wihuri Res Inst, Haartmaninkatu 8,POB 63, FI-00014 Helsinki, Finland;Univ Helsinki, Translat Canc Biol Program, Biomedicum Helsinki, Haartmaninkatu 8,POB 63, FI-00014 Helsinki, Finland.
    Zarb, Yvette
    Zurich Univ, Univ Zurich Hosp, Div Neurosurg, CH-8091 Zurich, Switzerland.
    Mochizuki, Naoki
    Natl Cerebral & Cardiovasc Ctr, Dept Cell Biol, Res Inst, 5-7-1 Fujishirodai, Suita, Osaka 5658565, Japan;Natl Cerebral & Cardiovasc Ctr, AMED CREST, 5-7-1 Fujishirodai, Suita, Osaka 5658565, Japan.
    Keller, Annika
    Zurich Univ, Univ Zurich Hosp, Div Neurosurg, CH-8091 Zurich, Switzerland.
    Lendahl, Urban
    Karolinska Inst, Dept Med Huddinge, Integrated Cardio Metab Ctr, Blickagangen 6, SE-14157 Huddinge, Sweden;Karolinska Inst, Dept Cell & Mol Biol, Von Eulers Vag 3, SE-17177 Stockholm, Sweden.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Dept Med Huddinge, Integrated Cardio Metab Ctr, Blickagangen 6, SE-14157 Huddinge, Sweden.
    Single-cell RNA sequencing of mouse brain and lung vascular and vessel-associated cell types2018In: Scientific Data, E-ISSN 2052-4463, Vol. 5, article id 180160Article in journal (Refereed)
    Abstract [en]

    Vascular diseases are major causes of death, yet our understanding of the cellular constituents of blood vessels, including how differences in their gene expression profiles create diversity in vascular structure and function, is limited. In this paper, we describe a single-cell RNA sequencing (scRNA-seq) dataset that defines vascular and vessel-associated cell types and subtypes in mouse brain and lung. The dataset contains 3,436 single cell transcriptomes from mouse brain, which formed 15 distinct clusters corresponding to cell (sub) types, and another 1,504 single cell transcriptomes from mouse lung, which formed 17 cell clusters. In order to allow user-friendly access to our data, we constructed a searchable database (http://betsholtzlab.org/VascularSingleCells/database.html). Our dataset constitutes a comprehensive molecular atlas of vascular and vessel-associated cell types in the mouse brain and lung, and as such provides a strong foundation for future studies of vascular development and diseases.

  • 23. Henderson, Neil C.
    et al.
    Arnold, Thomas D.
    Katamura, Yoshio
    Giacomini, Marilyn M.
    Rodriguez, Juan D.
    McCarty, Joseph H.
    Pellicoro, Antonella
    Raschperger, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Ruminski, Peter G.
    Griggs, David W.
    Prinsen, Michael J.
    Maher, Jacquelyn J.
    Iredale, John P.
    Lacy-Hulbert, Adam
    Adams, Ralf H.
    Sheppard, Dean
    Targeting of alpha(v) integrin identifies a core molecular pathway that regulates fibrosis in several organs2013In: Nature Medicine, ISSN 1078-8956, E-ISSN 1546-170X, Vol. 19, no 12, p. 1617-1624Article in journal (Refereed)
    Abstract [en]

    Myofibroblasts are the major source of extracellular matrix components that accumulate during tissue fibrosis, and hepatic stellate cells (HSCs) are believed to be the major source of myofibroblasts in the liver. To date, robust systems to genetically manipulate these cells have not been developed. We report that Cre under control of the promoter of Pdgfrb (Pdgfrb-Cre) inactivates loxP-flanked genes in mouse HSCs with high efficiency. We used this system to delete the gene encoding alpha(v) integrin subunit because various alpha(v)-containing integrins have been suggested as central mediators of fibrosis in multiple organs. Such depletion protected mice from carbon tetrachloride-induced hepatic fibrosis, whereas global loss of beta(3), beta(5) or beta(6) integrins or conditional loss of beta(8) integrins in HSCs did not. We also found that Pdgfrb-Cre effectively targeted myofibroblasts in multiple organs, and depletion of the alpha(v) integrin subunit using this system was protective in other models of organ fibrosis, including pulmonary and renal fibrosis. Pharmacological blockade of alpha(v)-containing integrins by a small molecule (CWHM 12) attenuated both liver and lung fibrosis, including in a therapeutic manner. These data identify a core pathway that regulates fibrosis and suggest that pharmacological targeting of all alpha(v) integrins may have clinical utility in the treatment of patients with a broad range of fibrotic diseases.

  • 24. Henshall, Tanya L
    et al.
    Keller, Annika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    He, Liqun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Johansson, Bengt R
    Wallgard, Elisabet
    Raschperger, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Mäe, Maarja Andaloussi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Jin, Shaobo
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Lendahl, Urban
    Notch3 Is Necessary for Blood Vessel Integrity in the Central Nervous System2015In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 35, no 2, p. 409-420Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Vascular smooth muscle cells (VSMC) are important for contraction, blood flow distribution, and regulation of blood vessel diameter, but to what extent they contribute to the integrity of blood vessels and blood-brain barrier function is less well understood. In this report, we explored the impact of the loss of VSMC in the Notch3(-/-) mouse on blood vessel integrity in the central nervous system.

    APPROACH AND RESULTS: Notch3(-/-) mice showed focal disruptions of the blood-brain barrier demonstrated by extravasation of tracers and accompanied by fibrin deposition in the retinal vasculature. This blood-brain barrier leakage was accompanied by a regionalized and patchy loss of VSMC, with VSMC gaps predominantly in arterial resistance vessels of larger caliber. The loss of VSMC appeared to be caused by progressive degeneration of VSMC resulting in a gradual loss of VSMC marker expression and a progressive acquisition of an aberrant VSMC phenotype closer to the gaps, followed by enhanced apoptosis and cellular disintegration in the gaps. Arterial VSMC were the only mural cell type that was morphologically affected, despite Notch3 being expressed also in pericytes. Transcriptome analysis of isolated brain microvessels revealed gene expression changes in Notch3(-/-) mice consistent with loss of arterial VSMC and presumably secondary transcriptional changes were observed in endothelial genes, which may explain the compromised vascular integrity.

    CONCLUSIONS: We demonstrate that Notch3 is important for survival of VSMC, and reveal a critical role for Notch3 and VSMC in blood vessel integrity and blood-brain barrier function in the mammalian vasculature.

  • 25.
    Honkura, Naoki
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Richards, Mark
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Laviña, Bàrbara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sainz-Jaspeado, Miguel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Intravital imaging-based analysis tools for vessel identification and assessment of concurrent dynamic vascular events2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 2746Article in journal (Refereed)
    Abstract [en]

    The vasculature undergoes changes in diameter, permeability and blood flow in response to specific stimuli. The dynamics and interdependence of these responses in different vessels are largely unknown. Here we report a non-invasive technique to study dynamic events in different vessel categories by multi-photon microscopy and an image analysis tool, RVDM (relative velocity, direction, and morphology) allowing the identification of vessel categories by their red blood cell (RBC) parameters. Moreover, Claudin5 promoter-driven green fluorescent protein (GFP) expression is used to distinguish capillary subtypes. Intradermal injection of vascular endothelial growth factor A (VEGFA) is shown to induce leakage of circulating dextran, with vessel-type-dependent kinetics, from capillaries and venules devoid of GFP expression. VEGFA-induced leakage in capillaries coincides with vessel dilation and reduced flow velocity. Thus, intravital imaging of non-invasive stimulation combined with RVDM analysis allows for recording and quantification of very rapid events in the vasculature.

  • 26.
    Ishibashi, Ryoichi
    et al.
    Chiba Univ, Grad Sch Med, Dept Clin Cell Biol & Med, Chiba, Japan.;Chiba Univ Hosp, Div Diabet Metab & Endocrinol, Chiba, Japan..
    Takemoto, Minoru
    Chiba Univ, Grad Sch Med, Dept Clin Cell Biol & Med, Chiba, Japan.;Chiba Univ Hosp, Div Diabet Metab & Endocrinol, Chiba, Japan..
    Akimoto, Yoshihiro
    Kyorin Univ, Sch Med, Dept Anat, Mitaka, Tokyo 181, Japan..
    Ishikawa, Takahiro
    Chiba Univ, Grad Sch Med, Dept Clin Cell Biol & Med, Chiba, Japan.;Chiba Univ Hosp, Div Diabet Metab & Endocrinol, Chiba, Japan..
    He, Peng
    Chiba Univ, Grad Sch Med, Dept Clin Cell Biol & Med, Chiba, Japan..
    Maezawa, Yoshiro
    Chiba Univ, Grad Sch Med, Dept Clin Cell Biol & Med, Chiba, Japan.;Chiba Univ Hosp, Div Diabet Metab & Endocrinol, Chiba, Japan..
    Sakamoto, Kenichi
    Chiba Univ, Grad Sch Med, Dept Clin Cell Biol & Med, Chiba, Japan.;Chiba Univ Hosp, Div Diabet Metab & Endocrinol, Chiba, Japan..
    Tsurutani, Yuya
    Yokohama Rosai Hosp, Yokohama, Kanagawa, Japan..
    Ide, Shintaro
    Chiba Univ, Grad Sch Med, Dept Clin Cell Biol & Med, Chiba, Japan.;Chiba Univ Hosp, Div Diabet Metab & Endocrinol, Chiba, Japan..
    Ide, Kana
    Chiba Univ, Grad Sch Med, Dept Clin Cell Biol & Med, Chiba, Japan.;Chiba Univ Hosp, Div Diabet Metab & Endocrinol, Chiba, Japan..
    Kawamura, Harukiyo
    Eastern Chiba Med Ctr, Chiba, Japan..
    Kobayashi, Kazuki
    Chiba Univ, Grad Sch Med, Dept Clin Cell Biol & Med, Chiba, Japan.;Chiba Univ Hosp, Div Diabet Metab & Endocrinol, Chiba, Japan..
    Tokuyama, Hirotake
    Yu Karigaoka Tokuyama Clin, Chiba, Japan..
    Tryggvason, Karl
    Duke NUS Grad Med Sch, Cardiovasc & Metab Disorders Program, Singapore, Singapore..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Yokote, Koutaro
    Chiba Univ, Grad Sch Med, Dept Clin Cell Biol & Med, Chiba, Japan.;Chiba Univ Hosp, Div Diabet Metab & Endocrinol, Chiba, Japan..
    A novel podocyte gene, semaphorin 3G, protects glomerular podocyte from lipopolysaccharide-induced inflammation2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 25955Article in journal (Refereed)
    Abstract [en]

    Kidney diseases including diabetic nephropathy have become huge medical problems, although its precise mechanisms are still far from understood. In order to increase our knowledge about the pathophysiology of kidney, we have previously identified >300 kidney glomerulus-enriched transcripts through large-scale sequencing and microarray profiling of the mouse glomerular transcriptome. One of the glomerulus-specific transcripts identified was semaphorin 3G (Sema3G) which belongs to the semaphorin family. The aim of this study was to analyze both the in vivo and in vitro functions of Sema3G in the kidney. Sema3G was expressed in glomerular podocytes. Although Sema3G knockout mice did not show obvious glomerular defects, ultrastructural analyses revealed partially aberrant podocyte foot processes structures. When these mice were injected with lipopolysaccharide to induce acute inflammation or streptozotocin to induce diabetes, the lack of Sema3G resulted in increased albuminuria. The lack of Sema3G in podocytes also enhanced the expression of inflammatory cytokines including chemokine ligand 2 and interleukin 6. On the other hand, the presence of Sema3G attenuated their expression through the inhibition of lipopolysaccharide-induced Toll like receptor 4 signaling. Taken together, our results surmise that the Sema3G protein is secreted by podocytes and protects podocytes from inflammatory kidney diseases and diabetic nephropathy.

  • 27. Ishikawa, T.
    et al.
    Takemoto, M.
    Akimoto, Y.
    Yan, K.
    Kenichi, S.
    He, P.
    Ishibashi, R.
    Maezawa, Y.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Tryggvason, K.
    Yokote, K.
    A novel podocyte gene, R3h domain containing-like inhibits non-canonical TGF-beta signalling2014In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 57, no S1, p. S44-S44Article in journal (Other academic)
  • 28.
    Jin, Yi
    et al.
    Karolinska Inst, Dept Med Biochem & Biophys, Scheeles Vag 2, S-17177 Stockholm, Sweden..
    Muhl, Lars
    Karolinska Inst, Dept Med Biochem & Biophys, Scheeles Vag 2, S-17177 Stockholm, Sweden..
    Burmakin, Mikhail
    Karolinska Inst, Dept Med Biochem & Biophys, Scheeles Vag 2, S-17177 Stockholm, Sweden..
    Wang, Yixin
    Karolinska Inst, Dept Med Biochem & Biophys, Scheeles Vag 2, S-17177 Stockholm, Sweden..
    Duchez, Anne-Claire
    Karolinska Inst, Dept Med Biochem & Biophys, Scheeles Vag 2, S-17177 Stockholm, Sweden..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, ICMC, Blickagangen 6, SE-14157 Huddinge, Sweden..
    Arthur, Helen M.
    Newcastle Univ, Inst Med Genet, Int Ctr Life, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England..
    Jakobsson, Lars
    Karolinska Inst, Dept Med Biochem & Biophys, Scheeles Vag 2, S-17177 Stockholm, Sweden..
    Endoglin prevents vascular malformation by regulating flow-induced cell migration and specification through VEGFR2 signalling2017In: Nature Cell Biology, ISSN 1465-7392, E-ISSN 1476-4679, Vol. 19, no 6, p. 639-652Article in journal (Refereed)
    Abstract [en]

    Loss-of-function (LOF) mutations in the endothelial cell (EC)-enriched gene endoglin (ENG) cause the human disease hereditary haemorrhagic telangiectasia-1, characterized by vascular malformations promoted by vascular endothelial growth factor A (VEGFA). How ENG deficiency alters EC behaviour to trigger these anomalies is not understood. Mosaic ENG deletion in the postnatal mouse rendered Eng LOF ECs insensitive to flow-mediated venous to arterial migration. Eng LOF ECs retained within arterioles acquired venous characteristics and secondary ENG-independent proliferation resulting in arteriovenous malformation (AVM). Analysis following simultaneous Eng LOF and overexpression (OE) revealed that ENG OE ECs dominate tip-cell positions and home preferentially to arteries. ENG knockdown altered VEGFA-mediated VEGFR2 kinetics and promoted AKT signalling. Blockage of PI(3)K/AKT partly normalized flow-directed migration of ENG LOF ECs in vitro and reduced the severity of AVM in vivo. This demonstrates the requirement of ENG in flow-mediated migration and modulation of VEGFR2 signalling in vascular patterning.

  • 29.
    Jones, Gregory T.
    et al.
    Univ Otago, Dept Surg, Dunedin 9054, New Zealand..
    Tromp, Gerard
    Geisinger Hlth Syst, Sigfried & Janet Weis Ctr Res, Danville, PA USA.;Univ Stellenbosch, Dept Biomed Sci, Fac Med & Hlth Sci, Div Mol Biol & Human Genet, Tygerberg, South Africa.;deCODE Amgen, Reykjavik, Iceland..
    Kuivaniemi, Helena
    Geisinger Hlth Syst, Sigfried & Janet Weis Ctr Res, Danville, PA USA.;Univ Stellenbosch, Dept Biomed Sci, Fac Med & Hlth Sci, Div Mol Biol & Human Genet, Tygerberg, South Africa..
    Gretarsdottir, Solveig
    Baas, Annette F.
    Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands..
    Giusti, Betti
    Univ Florence, Careggi Hosp, Dept Expt & Clin Med, Atherothrombot Dis Ctr, Florence, Italy..
    Strauss, Ewa
    Polish Acad Sci, Inst Human Genet, Fac Nucle Acid Funct, Poznan, Poland.;Poznan Univ Med Sci, Dept Gen & Vasc Surg, Poznan, Poland..
    van't Hof, Femke N. G.
    Webb, Thomas R.
    Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England.;Glenfield Gen Hosp, NIHR Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England..
    Erdman, Robert
    Geisinger Hlth Syst, Sigfried & Janet Weis Ctr Res, Danville, PA USA..
    Ritchie, Marylyn D.
    Geisinger Hlth Syst, Biomed & Translat Informat, Danville, PA USA.;Penn State Univ, University Pk, PA 16802 USA..
    Elmore, James R.
    Geisinger Med Ctr, Dept Vasc Surg, Danville, PA 17822 USA..
    Verma, Anurag
    Penn State Univ, University Pk, PA 16802 USA..
    Pendergrass, Sarah
    Geisinger Hlth Syst, Biomed & Translat Informat, Danville, PA USA.;Penn State Univ, University Pk, PA 16802 USA..
    Kullo, Iftikhar J.
    Mayo Clin Rochester, Rochester, MN USA..
    Zy, Zi Ye
    Mayo Clin Rochester, Rochester, MN USA..
    Peissig, Peggy L.
    Marshfield Clin Res Fdn, Marshfield, WI USA..
    Gottesman, Omri
    Icahn Sch Med Mt Sinai, New York, NY 10029 USA..
    Verma, Shefali S.
    Penn State Univ, University Pk, PA 16802 USA..
    Malinowski, Jennifer
    Vanderbilt Univ, 221 Kirkland Hall, Nashville, TN 37235 USA..
    Rasmussen-Torvik, Laura J.
    Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA..
    Borthwick, Kenneth M.
    Geisinger Hlth Syst, Sigfried & Janet Weis Ctr Res, Danville, PA USA..
    Smelser, Diane T.
    Geisinger Hlth Syst, Sigfried & Janet Weis Ctr Res, Danville, PA USA..
    Crosslin, David R.
    Univ Washington, Dept Biomed Informat & Med Educ, Seattle, WA 98195 USA..
    de Andrade, Mariza
    Mayo Clin Rochester, Rochester, MN USA..
    Ryer, Evan J.
    Geisinger Med Ctr, Dept Vasc Surg, Danville, PA 17822 USA..
    McCarty, Catherine A.
    Essentia Inst Rural Hlth, Div Res, Duluth, MN USA..
    Bottinger, Erwin P.
    Icahn Sch Med Mt Sinai, New York, NY 10029 USA..
    Pacheco, Jennifer A.
    Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA..
    Crawford, Dana C.
    Case Western Reserve Univ, Cleveland, OH 44106 USA..
    Carrell, David S.
    Grp Hlth Res Inst, Seattle, WA USA..
    Gerhard, Glenn S.
    Temple Univ, Sch Med, Dept Med Genet & Mol Biochem, Philadelphia, PA 19122 USA..
    Franklin, David P.
    Mission Hlth Syst, Mission Clin, Asheville, NC USA..
    Carey, David J.
    Geisinger Hlth Syst, Sigfried & Janet Weis Ctr Res, Danville, PA USA..
    Phillips, Victoria L.
    Univ Otago, Dept Surg, Dunedin 9054, New Zealand..
    Williams, Michael J. A.
    Univ Otago, Dept Med, Dunedin, New Zealand..
    Wei, Wenhua
    Univ Otago, Dept Surg, Dunedin 9054, New Zealand..
    Blair, Ross
    Waikato Hosp, Hamilton, New Zealand..
    Hill, Andrew A.
    Auckland City Hosp, Auckland, New Zealand..
    Vasudevan, Thodor M.
    Waikato Hosp, Hamilton, New Zealand..
    Lewis, David R.
    Univ Otago, Dept Surg, Christchurch, New Zealand..
    Thomson, Ian A.
    Univ Otago, Dept Surg, Dunedin 9054, New Zealand..
    Krysa, Jo
    Univ Otago, Dept Surg, Dunedin 9054, New Zealand..
    Hill, Geraldine B.
    Univ Otago, Dept Surg, Dunedin 9054, New Zealand..
    Roake, Justin
    Univ Otago, Dept Surg, Christchurch, New Zealand..
    Merriman, Tony R.
    Univ Otago, Dept Biochem, Dunedin, New Zealand..
    Oszkinis, Grzegorz
    Poznan Univ Med Sci, Dept Gen & Vasc Surg, Poznan, Poland..
    Galora, Silvia
    deCODE Amgen, Reykjavik, Iceland.;Univ Florence, Careggi Hosp, Dept Expt & Clin Med, Atherothrombot Dis Ctr, Florence, Italy..
    Saracini, Claudia
    Univ Florence, Careggi Hosp, Dept Expt & Clin Med, Atherothrombot Dis Ctr, Florence, Italy..
    Abbate, Rosanna
    Univ Florence, Careggi Hosp, Dept Expt & Clin Med, Atherothrombot Dis Ctr, Florence, Italy..
    Pulli, Raffaele
    Univ Florence, Careggi Hosp, Dept Expt & Clin Med, Vasc Surg Unit, Florence, Italy..
    Pratesi, Carlo
    Univ Florence, Careggi Hosp, Dept Expt & Clin Med, Vasc Surg Unit, Florence, Italy..
    Saratzis, Athanasios
    Verissimo, Ana R.
    Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England.;Glenfield Gen Hosp, NIHR Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England..
    Bumpstead, Suzannah
    Wellcome Trust Sanger Inst, Genet Complex Traits Humans Grp, Cambridge, England..
    Badger, Stephen A.
    Queens Univ Belfast, Sch Med, Belfast, Antrim, North Ireland..
    Clough, Rachel E.
    Kings Coll London, Dept Vasc Surg, London, England. Kings Coll London, British Heart Fdn Ctr Res Excellence, Cardiovasc Div, Dept Vasc Surg, London, England..
    Cockerill, Gillian
    St Georges Univ London, Dept Vasc Surg, London, England..
    Hafez, Hany
    King Faisal Specialist Hosp & Res Ctr, Jeddah, Saudi Arabia..
    Scott, D. Julian A.
    Univ Leeds, Leeds Inst Cardiovasc & Metab Med, Leeds, W Yorkshire, England..
    Futers, T. Simon
    Univ Leeds, Leeds Inst Cardiovasc & Metab Med, Leeds, W Yorkshire, England..
    Romaine, Simon P. R.
    Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England.;Univ Leeds, Leeds Inst Cardiovasc & Metab Med, Leeds, W Yorkshire, England..
    Bridge, Katherine
    Univ Leeds, Leeds Inst Cardiovasc & Metab Med, Leeds, W Yorkshire, England..
    Griffin, Kathryn J.
    Univ Leeds, Leeds Inst Cardiovasc & Metab Med, Leeds, W Yorkshire, England..
    Bailey, Marc A.
    Univ Leeds, Leeds Inst Cardiovasc & Metab Med, Leeds, W Yorkshire, England..
    Smith, Alberto
    Thompson, Matthew M.
    St Georges Univ London, Dept Vasc Surg, London, England..
    van Bockxmeer, Frank M.
    Univ Western Australia, Dept Surg, Crawley, Australia..
    Matthiasson, Stefan E.
    Laekning Med Clin, Reykjavik, Iceland..
    Thorleifsson, Gudmar
    Thorsteinsdottir, Unnur
    deCODE Amgen, Reykjavik, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Blankensteijn, Jan D.
    Vrije Univ Amsterdam Med Ctr, Dept Vasc Surg, Amsterdam, Netherlands..
    Teijink, Joep A. W.
    Maastricht Univ, CAPHRI Res Sch, Eindhoven, Netherlands.;Catharina Hosp, Dept Vasc Surg, Eindhoven, Netherlands..
    Wijmenga, Cisca
    Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands..
    de Graaf, Jacqueline
    Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Nijmegen, Netherlands..
    Kiemeney, Lambertus A.
    Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Nijmegen, Netherlands..
    Lindholt, Jes S.
    Odense Univ Hosp, Dept Cardiothorac & Vasc Surg, Elitary Res Ctr Individualized Med Arterial Dis C, Odense, Denmark..
    Hughes, Anne
    Bradley, Declan T.
    Queens Univ Belfast, Ctr Publ Hlth, Belfast, Antrim, North Ireland..
    Stirrups, Kathleen
    Golledge, Jonathan
    James Cook Univ, Queensland Res Ctr Peripheral Vasc Dis, Vasc Biol Unit, Townsville, Qld, Australia.;James Cook Univ, Dept Vasc & Endovasc Surg, Townsville, Qld, Australia.;Townsville Hosp, Townsville, Qld, Australia..
    Norman, Paul E.
    Univ Western Australia, Dept Surg, Crawley, Australia..
    Powell, Janet T.
    Imperial Coll London, Dept Surg & Canc, London, England. UCL, Inst Cardiovasc Sci, Cardiovasc Genet, London, England..
    Humphries, Steve E.
    Hamby, Stephen E.
    Goodall, Alison H.
    Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England.;Glenfield Gen Hosp, NIHR Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England..
    Nelson, Christopher P.
    Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England.;Glenfield Gen Hosp, NIHR Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England..
    Sakalihasan, Natzi
    Univ Liege, Surg Res Ctr, GIGA Cardiovasc Sci Unit, Liege, Belgium..
    Courtois, Audrey
    Univ Florence, Careggi Hosp, Dept Expt & Clin Med, Atherothrombot Dis Ctr, Florence, Italy..
    Ferrell, Robert E.
    Univ Pittsburgh, Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15260 USA..
    Eriksson, Per
    Karolinska Inst, Dept Med, Ctr Mol Med, Atherosclerosis Res Unit, Stockholm, Sweden..
    Folkersen, Lasse
    Karolinska Inst, Dept Med, Ctr Mol Med, Atherosclerosis Res Unit, Stockholm, Sweden.;Tech Univ Denmark, Ctr Biol Sequence Anal, Copenhagen, Denmark..
    Franco-Cereceda, Anders
    Karolinska Inst, Dept Mol Med & Surg, Cardiothorac Surg Unit, Stockholm, Sweden..
    Eicher, John D.
    NHLBI, Ctr Populat Studies, Framingham Heart Study, Framingham, MA USA..
    Johnson, Andrew D.
    NHLBI, Ctr Populat Studies, Framingham Heart Study, Framingham, MA USA..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Dept Med Biochem & Biophys, Vasc Biol Unit, Stockholm, Sweden..
    Ruusalepp, Arno
    deCODE Amgen, Reykjavik, Iceland.;Tartu Univ Hosp, Dept Cardiac Surg, Tartu, Estonia.;Clin Gene Networks AB, Stockholm, Sweden..
    Franzen, Oscar
    Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, Inst Genom & Multiscale Biol, New York, NY 10029 USA.;Clin Gene Networks AB, Stockholm, Sweden..
    Schadt, Eric E.
    Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, Inst Genom & Multiscale Biol, New York, NY 10029 USA..
    Bjorkegren, Johan L. M.
    Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, Inst Genom & Multiscale Biol, New York, NY 10029 USA.;Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden.;Univ Tartu, Inst Biomed & Translat Med, Dept Physiol, Tartu, Estonia.;Clin Gene Networks AB, Stockholm, Sweden..
    Lipovich, Leonard
    Wayne State Univ, Dept Neurol, Detroit, MI USA..
    Drolet, Anne M.
    Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA..
    Verhoeven, Eric L.
    Paracelsus Med Univ Nuremberg, Dept Vasc & Endovasc Surg, Nurnberg, Germany..
    Zeebregts, Clark J.
    Univ Groningen, Univ Med Ctr Groningen, Dept Surg, Div Vasc Surg, Groningen, Netherlands..
    Geelkerken, Robert H.
    Chirurgencooperatie Oost Nederland, Enschede, Netherlands..
    van Sambeek, Marc R.
    Catharina Hosp, Dept Vasc Surg, Eindhoven, Netherlands..
    van Sterkenburg, Steven M.
    TweeSteden Hosp, Dept Surg, Tilburg, Netherlands.;Rijnstate Ziekenhuis, Dept Vasc Surg, Arnhem, Netherlands..
    de Vries, Jean-Paul
    St Antonius Hosp, Dept Vasc Surg, Nieuwegein, Netherlands..
    Stefansson, Kari
    Thompson, John R.
    Univ Leicester, Dept Hlth Sci, Leicester, Leics, England..
    de Bakker, Paul I. W.
    Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands.;Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Dept Epidemiol, Utrecht, Netherlands..
    Deloukas, Panos
    Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England. Univ Cambridge, Dept Haematol, Cambridge, England.;King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah, Saudi Arabia..
    Sayers, Robert D.
    Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England..
    Harrison, Seamus C.
    Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England..
    van Rij, Andre M.
    Univ Otago, Dept Surg, Dunedin 9054, New Zealand..
    Samani, Nilesh J.
    Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England.;Glenfield Gen Hosp, NIHR Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England..
    Bown, Matthew J.
    Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England.;Glenfield Gen Hosp, NIHR Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England..
    Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci2017In: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 120, no 2, p. 341-+Article in journal (Refereed)
    Abstract [en]

    Rationale: Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA. Objective: To identify additional AAA risk loci using data from all available genome-wide association studies. Methods and Results: Through a meta-analysis of 6 genome-wide association study data sets and a validation study totaling 10 204 cases and 107 766 controls, we identified 4 new AAA risk loci: 1q32.3 (SMYD2), 13q12.11 (LINC00540), 20q13.12 (near PCIF1/MMP9/ZNF335), and 21q22.2 (ERG). In various database searches, we observed no new associations between the lead AAA single nucleotide polymorphisms and coronary artery disease, blood pressure, lipids, or diabetes mellitus. Network analyses identified ERG, IL6R, and LDLR as modifiers of MMP9, with a direct interaction between ERG and MMP9. Conclusions: The 4 new risk loci for AAA seem to be specific for AAA compared with other cardiovascular diseases and related traits suggesting that traditional cardiovascular risk factor management may only have limited value in preventing the progression of aneurysmal disease.

  • 30.
    Jung, Bongnam
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Arnold, Thomas D.
    Univ Calif San Francisco, Dept Pediat, San Francisco, CA USA.
    Raschperger, Elisabeth
    Novum, Karolinska Inst, ICMC, Stockholm, Sweden.
    Gaengel, Konstantin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Novum, Karolinska Inst, ICMC, Stockholm, Sweden.
    Visualization of vascular mural cells in developing brain using genetically labeled transgenic reporter mice2018In: Journal of Cerebral Blood Flow and Metabolism, ISSN 0271-678X, E-ISSN 1559-7016, Vol. 38, no 3, p. 456-468Article in journal (Refereed)
    Abstract [en]

    The establishment of a fully functional blood vascular system requires elaborate angiogenic and vascular maturation events in order to fulfill organ-specific anatomical and physiological needs. Although vascular mural cells, i.e. pericytes and vascular smooth muscle cells, are known to play fundamental roles during these processes, their characteristics during vascular development remain incompletely understood. In this report, we utilized transgenic reporter mice in which mural cells are genetically labeled to examine developing vascular mural cells in the central nervous system (CNS). We found platelet-derived growth factor receptor beta gene (Pdgfrb)-driven EGFP reporter expression as a suitable marker for vascular mural cells at the earliest stages of mouse brain vascularization. Furthermore, the combination of Pdgfrb and NG2 gene (Cspg4) driven reporter expression increased the specificity of brain vascular mural cell labeling at later stages. The expression of other known pericyte markers revealed time-,region-and marker-specific patterns, suggesting heterogeneity in mural cell maturation. We conclude that transgenic reporter mice provide an important tool to explore the development of CNS pericytes in health and disease.

  • 31.
    Keller, A.
    et al.
    Univ Zurich, Dept Neurosurg, Zurich, Switzerland..
    Zarb, Y.
    Univ Zurich, Dept Neurosurg, Zurich, Switzerland..
    Johannson, B.
    Gothenburg Univ, Dept Biochem & Cell Biol, Gothenburg, Sweden..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Greter, M.
    Univ Zurich, Inst Expt Immunol, Zurich, Switzerland..
    Colonna, M.
    Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO USA..
    The role of microglia in microvascular calcification in the brain2017In: Glia, ISSN 0894-1491, E-ISSN 1098-1136, Vol. 65, no S1, p. E509-E509Article in journal (Other academic)
  • 32.
    Keller, Annika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Westenberger, Ana
    Sobrido, Maria J.
    Garcia-Murias, Maria
    Domingo, Aloysius
    Sears, Renee L.
    Lemos, Roberta R.
    Ordonez-Ugalde, Andres
    Nicolas, Gael
    Gomes da Cunha, Jose E.
    Rushing, Elisabeth J.
    Hugelshofer, Michael
    Wurnig, Moritz C.
    Kaech, Andres
    Reimann, Regina
    Lohmann, Katja
    Dobricic, Valerija
    Carracedo, Angel
    Petrovic, Igor
    Miyasaki, Janis M.
    Abakumova, Irina
    Mäe, Maarja Andaloussi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Raschperger, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Zatz, Mayana
    Zschiedrich, Katja
    Klepper, Jorg
    Spiteri, Elizabeth
    Prieto, Jose M.
    Navas, Inmaculada
    Preuss, Michael
    Dering, Carmen
    Jankovic, Milena
    Paucar, Martin
    Svenningsson, Per
    Saliminejad, Kioomars
    Khorshid, Hamid R. K.
    Novakovic, Ivana
    Aguzzi, Adriano
    Boss, Andreas
    Le Ber, Isabelle
    Defer, Gilles
    Hannequin, Didier
    Kostic, Vladimir S.
    Campion, Dominique
    Geschwind, Daniel H.
    Coppola, Giovanni
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Klein, Christine
    Oliveira, Joao R. M.
    Mutations in the gene encoding PDGF-B cause brain calcifications in humans and mice2013In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 45, no 9, p. 1077-+Article in journal (Refereed)
    Abstract [en]

    Calcifications in the basal ganglia are a common incidental finding and are sometimes inherited as an autosomal dominant trait ( idiopathic basal ganglia calcification (IBGC)). Recently, mutations in the PDGFRB gene coding for the platelet-derived growth factor receptor beta (PDGF-R beta) were linked to IBGC. Here we identify six families of different ancestry with nonsense and missense mutations in the gene encoding PDGF-B, the main ligand for PDGF-R beta. We also show that mice carrying hypomorphic Pdgfb alleles develop brain calcifications that show age-related expansion. The occurrence of these calcium depositions depends on the loss of endothelial PDGF-B and correlates with the degree of pericyte and blood-brain barrier deficiency. Thus, our data present a clear link between Pdgfb mutations and brain calcifications in mice, as well as between PDGFB mutations and IBGC in humans.

  • 33. Kok, Fatma O.
    et al.
    Shin, Masahiro
    Ni, Chih-Wen
    Gupta, Ankit
    Grosse, Ann S.
    van Impel, Andreas
    Kirchmaier, Bettina C.
    Peterson-Maduro, Josi
    Kourkoulis, George
    Male, Ira
    DeSantis, Dana F.
    Sheppard-Tindell, Sarah
    Ebarasi, Lwaki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Schulte-Merker, Stefan
    Wolfe, Scot A.
    Lawson, Nathan D.
    Reverse Genetic Screening Reveals Poor Correlation between Morpholino-Induced and Mutant Phenotypes in Zebrafish2015In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 32, no 1, p. 97-108Article in journal (Refereed)
    Abstract [en]

    The widespread availability of programmable site-specific nucleases now enables targeted gene disruption in the zebrafish. In this study, we applied site-specific nucleases to generate zebrafish lines bearing individual mutations in more than 20 genes. We found that mutations in only a small proportion of genes caused defects in embryogenesis. Moreover, mutants for ten different genes failed to recapitulate published Morpholino-induced phenotypes (morphants). The absence of phenotypes in mutant embryos was not likely due to maternal effects or failure to eliminate gene function. Consistently, a comparison of published morphant defects with the Sanger Zebrafish Mutation Project revealed that approximately 80% of morphant phenotypes were not observed in mutant embryos, similar to our mutant collection. Based on these results, we suggest that mutant phenotypes become the standard metric to define gene function in zebrafish, after which Morpholinos that recapitulate respective phenotypes could be reliably applied for ancillary analyses.

  • 34.
    Kusumbe, Anjali P.
    et al.
    Max Planck Inst Mol Biomed, Dept Tissue Morphogenesis, D-48149 Munster, Germany.;Univ Munster, Fac Med, D-48149 Munster, Germany..
    Ramasamy, Saravana K.
    Max Planck Inst Mol Biomed, Dept Tissue Morphogenesis, D-48149 Munster, Germany.;Univ Munster, Fac Med, D-48149 Munster, Germany..
    Itkin, Tomer
    Weizmann Inst Sci, Dept Immunol, IL-76100 Rehovot, Israel..
    Mae, Maarja Andaloussi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Langen, Urs H.
    Max Planck Inst Mol Biomed, Dept Tissue Morphogenesis, D-48149 Munster, Germany.;Univ Munster, Fac Med, D-48149 Munster, Germany..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Lapidot, Tsvee
    Weizmann Inst Sci, Dept Immunol, IL-76100 Rehovot, Israel..
    Adams, Ralf H.
    Max Planck Inst Mol Biomed, Dept Tissue Morphogenesis, D-48149 Munster, Germany.;Univ Munster, Fac Med, D-48149 Munster, Germany..
    Age-dependent modulation of vascular niches for haematopoietic stem cells2016In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 532, no 7599, p. 380-+Article in journal (Refereed)
    Abstract [en]

    Blood vessels define local microenvironments in the skeletal system, play crucial roles in osteogenesis and provide niches for haematopoietic stem cells(1-6). The properties of nicheforming vessels and their changes in the ageing organism remain incompletely understood. Here we show that Notch signalling in endothelial cells leads to the expansion of haematopoietic stem cell niches in bone, which involves increases in CD31-positive capillaries and platelet-derived growth factor receptor-beta (PDGFR beta)-positive perivascular cells, arteriole formation and elevated levels of cellular stem cell factor. Although endothelial hypoxia-inducible factor signalling promotes some of these changes, it fails to enhance vascular niche function because of a lack of arterialization and expansion of PDGFR beta-positive cells. In ageing mice, niche-forming vessels in the skeletal system are strongly reduced but can be restored by activation of endothelial Notch signalling. These findings indicate that vascular niches for haematopoietic stem cells are part of complex, age-dependent microenvironments involving multiple cell populations and vessel subtypes.

  • 35.
    Laviña, Bàrbara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Castro, Marco
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Niaudet, Colin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Bert, Cruys
    Peter, Carmeliet
    Bentley, Katie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. 4Computational Biology Laboratory, Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA.
    Cord, Brakebusch
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Gängel, Konstantin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Defective endothelial cell migration in the absence of Cdc42 leads to capillary-venous malformations: Cdc42 and vascular malformationsManuscript (preprint) (Other academic)
  • 36.
    Laviña, Bàrbara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Castro, Marco
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Niaudet, Colin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Cruys, Bert
    VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Leuven, Belgium; Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Leuven, Belgium.
    Álvarez-Aznar, Alberto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Carmeliet, Peter
    VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Leuven, Belgium; Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Leuven, Belgium.
    Bentley, Katie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Harvard Med Sch, Beth Israel Deaconess Med Ctr, Ctr Vasc Biol Res, Computat Biol Lab, Boston, MA USA.
    Brakebusch, Cord
    Univ Copenhagen, Biotech Res & Innovat Ctr, Copenhagen, Denmark.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Dept Med Huddinge, ICMC, Stockholm, Sweden.
    Gängel, Konstantin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Defective endothelial cell migration in the absence of Cdc42 leads to capillary-venous malformations2018In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 145, no 13, article id UNSP dev161182Article in journal (Refereed)
    Abstract [en]

    Formation and homeostasis of the vascular system requires several coordinated cellular functions, but their precise interplay during development and their relative importance for vascular pathologies remain poorly understood. Here, we investigated the endothelial functions regulated by Cdc42 and their in vivo relevance during angiogenic sprouting and vascular morphogenesis in the postnatal mouse retina. We found that Cdc42 is required for endothelial tip cell selection, directed cell migration and filopodia formation, but dispensable for cell proliferation or apoptosis. Although the loss of Cdc42 seems generally compatible with apical-basal polarization and lumen formation in retinal blood vessels, it leads to defective endothelial axial polarization and to the formation of severe vascular malformations in capillaries and veins. Tracking of Cdc42-depleted endothelial cells in mosaic retinas suggests that these capillary-venous malformations arise as a consequence of defective cell migration, when endothelial cells that proliferate at normal rates are unable to re-distribute within the vascular network.

  • 37.
    Li, Xiujuan
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Padhan, Narendra
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala Univ, Sci Life Lab, Rudbeck Lab, Dept Immunol Genet & Pathol, S-75185 Uppsala, Sweden..
    Sjöström, Elisabet O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala Univ, Sci Life Lab, Rudbeck Lab, Dept Immunol Genet & Pathol, S-75185 Uppsala, Sweden..
    Roche, Francis P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Testini, Chiara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Honkura, Naoki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sainz-Jaspeado, Miguel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gordon, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bentley, Katie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab. Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, 330 Brookline Ave, Boston, MA 02215 USA..
    Philippides, Andrew
    Univ Sussex, Ctr Computat Neurosci & Robot, Chichester 1 CI 104, Brighton BN1 9RH, E Sussex, England..
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab. IFOM IEO Campus, Via Adamello 16, I-20139 Milan, Italy..
    Stan, Radu V.
    Dartmouth Coll, Dept Pathol, Geisel Sch Med Dartmouth, Lebanon, NH 03756 USA..
    Vestweber, Dietmar
    Max Planck Inst Mol Biomed, Dept Vasc Cell Biol, Rontgenstr 20, D-48149 Munster, Germany..
    Ballmer-Hofer, Kurt
    Paul Scherrer Inst, Biomol Res, Mol Cell Biol, CH-5232 Villigen, Switzerland..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, S-17177 Stockholm, Sweden..
    Pietras, Kristian
    Lund Univ, Medicon Village, Translat Canc Res, Bldg 404-A3, S-22381 Lund, Sweden..
    Jansson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread2016In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, article id 11017Article in journal (Refereed)
    Abstract [en]

    The specific role of VEGFA-induced permeability and vascular leakage in physiology and pathology has remained unclear. Here we show that VEGFA-induced vascular leakage depends on signalling initiated via the VEGFR2 phosphosite Y949, regulating dynamic c-Src and VE-cadherin phosphorylation. Abolished Y949 signalling in the mouse mutant Vegfr2(Y949F/Y949F) leads to VEGFA-resistant endothelial adherens junctions and a block in molecular extravasation. Vessels in Vegfr2(Y949F/Y949F) mice remain sensitive to inflammatory cytokines, and vascular morphology, blood pressure and flow parameters are normal. Tumour-bearing Vegfr2(Y949F/Y949F) mice display reduced vascular leakage and oedema, improved response to chemotherapy and, importantly, reduced metastatic spread. The inflammatory infiltration in the tumour micro-environment is unaffected. Blocking VEGFA-induced disassembly of endothelial junctions, thereby suppressing tumour oedema and metastatic spread, may be preferable to full vascular suppression in the treatment of certain cancer forms.

  • 38.
    Liu, Peidi
    et al.
    Univ Gothenburg, Inst Neurosci & Physiol, Dept Physiol, Gothenburg, Sweden..
    Lassen, Emelie
    Univ Gothenburg, Inst Neurosci & Physiol, Dept Physiol, Gothenburg, Sweden..
    Nair, Viji
    Univ Michigan, Dept Internal Med, Div Nephrol, Ann Arbor, MI 48109 USA.;Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA..
    Berthier, Celine C.
    Univ Michigan, Dept Internal Med, Div Nephrol, Ann Arbor, MI 48109 USA.;Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA..
    Suguro, Miyuki
    Aichi Canc Ctr Res Inst, Div Mol Med, Nagoya, Aichi, Japan..
    Sihlbom, Carina
    Univ Gothenburg, Prote Core Facil, Gothenburg, Sweden..
    Kretzler, Matthias
    Univ Michigan, Dept Internal Med, Div Nephrol, Ann Arbor, MI 48109 USA.;Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst Novum, Integrated Cardio Metab Ctr, Huddinge, Sweden..
    Haraldsson, Borje
    Univ Gothenburg, Inst Neurosci & Physiol, Dept Physiol, Gothenburg, Sweden..
    Ju, Wenjun
    Univ Michigan, Dept Internal Med, Div Nephrol, Ann Arbor, MI 48109 USA.;Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA..
    Ebefors, Kerstin
    Univ Gothenburg, Inst Neurosci & Physiol, Dept Physiol, Gothenburg, Sweden..
    Nystrom, Jenny
    Univ Gothenburg, Inst Neurosci & Physiol, Dept Physiol, Gothenburg, Sweden..
    Transcriptomic and Proteomic Profiling Provides Insight into Mesangial Cell Function in IgA Nephropathy2017In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 28, no 10, p. 2961-2972Article in journal (Refereed)
    Abstract [en]

    IgA nephropathy (IgAN), the most common GN worldwide, is characterized by circulating galactose-deficient IgA (gd-IgA) that forms immune complexes. The immune complexes are deposited in the glomerular mesangium, leading to inflammation and loss of renal function, but the complete pathophysiology of the disease is not understood. Using an integrated global transcriptomic and proteomic profiling approach, we investigated the role of the mesangium in the onset and progression of IgAN. Global gene expression was investigated by microarray analysis of the glomerular compartment of renal biopsy specimens from patients with IgAN (n=19) and controls (n=22). Using curated glomerular cell type specific genes from the published literature, we found differential expression of a much higher percentage of mesangial cell positive standard genes than podocyte-positive standard genes in IgAN. Principal coordinate analysis of expression data revealed clear separation of patient and control samples on the basis of mesangial but not podocyte cell positive standard genes. Additionally, patient clinical parameters (serum creatinine values and eGFRs) significantly correlated with Z scores derived from the expression profile of mesangial cell positive standard genes. Among patients grouped according to Oxford MEST score, patients with segmental glomerulosclerosis had a significantly higher mesangial cell positive standard gene Z score than patients without segmental glomerulosclerosis. By investigating mesangial cell proteomics and glomerular transcriptomics, we identified 22 common pathways induced in mesangial cells by gd-IgA, most of which mediate inflammation. The genes, proteins, and corresponding pathways identified provide novel insights into the pathophysiologic mechanisms leading to IgAN.

  • 39.
    Loganathan, Krishnapriya
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Salem Said, Ebtisam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Winterrowd, Emily
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Orebrand, Martina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    He, Liqun
    Department of Neurosur gery, Tianjin Medical University General Hospital, Tianjin Neurolo gical Institute, Key Laborat ory of Post-Neur oinjury Neuro-Rep air and Regener ation in Central Nervous System, Ministry of Educatio n and Tianjin City, Tianjin, China,.
    Vanlandewijck, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. ntegrated Cardio Metabolic Centre, Karolinska Institutet, Huddinge , Sweden.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. ntegrated Cardio Metabolic Centre, Karolinska Institutet, Huddinge , Sweden.
    Quaggin, Susan E
    Feinberg Cardiovas cular Research Institute, Northwestern University , Chicago, United States of America.
    Jeansson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Angiopoietin-1 deficiency increases renal capillary rarefaction and tubulointerstitial fibrosis in mice2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 1, article id e0189433Article in journal (Refereed)
    Abstract [en]

    Presence of tubulointerstitial fibrosis is predictive of progressive decline in kidney function, independent of its underlying cause. Injury to the renal microvasculature is a major factor in the progression of fibrosis and identification of factors that regulate endothelium in fibrosis is desirable as they might be candidate targets for treatment of kidney diseases. The current study investigates how loss of Angipoietin-1 (Angpt1), a ligand for endothelial tyrosine-kinase receptor Tek (also called Tie2), affects tubulointerstitial fibrosis and renal microvasculature. Inducible Angpt1 knockout mice were subjected to unilateral ureteral obstruction (UUO) to induce fibrosis, and kidneys were collected at different time points up to 10 days after obstruction. Staining for aSMA showed that Angpt1 deficient kidneys had significantly more fibrosis compared to wildtype mice 3, 6, and 10 days after UUO. Further investigation 3 days after UUO showed a significant increase of Col1a1 and vimentin in Angpt1 deficient mice, as well as increased gene expression of Tgfb1, Col1a1, Fn1, and CD44. Kidney injury molecule 1 (Kim1/Havcr1) was significantly more increased in Angpt1 deficient mice 1 and 3 days after UUO, suggesting a more severe injury early in the fibrotic process in Angpt1 deficient mice. Staining for endomucin showed that capillary rarefaction was evident 3 days after UUO and Angpt1 deficient mice had significantly less capillaries 6 and 10 days after UUO compared to UUO kidneys in wildtype mice. RNA sequencing revealed downregulation of several markers for endothelial cells 3 days after UUO, and that Angpt1 deficient mice had a further downregulation of Emcn, Plvap, Pecam1, Erg, and Tek. Our results suggest that loss of Angpt1 is central in capillary rarefaction and fibrogenesis and propose that manipulations to maintain Angpt1 levels may slow down fibrosis progression.

  • 40.
    Mihajlica, Nebojsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Pharmacokinetics of Pericyte Involvement in Small-Molecular Drug Transport Across the Blood-Brain Barrier2018In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 122, p. 77-84Article in journal (Refereed)
    Abstract [en]

    Pericytes are perivascular cells that play important roles in the regulation of the blood-brain barrier (BBB) properties. Pericyte-deficiency causes compromised BBB integrity and increase in permeability to different macromolecules mainly by upregulated transcytosis. The aim of the present study was to investigate pericyte involvement in the extent of small-molecular drug transport across the BBB. This was performed with five compounds: diazepam, digoxin, levofloxacin, oxycodone and paliperidone. Compounds were administered at low doses via subcutaneous injections as a cassette (simultaneously) to pericyte-deficient Pdgfb(ret/ret) mice and corresponding WT controls. Total drug partitioning across the BBB was calculated as the ratio of total drug exposures in brain tissue and plasma (K-p,K-brain). In addition, equilibrium dialysis experiments were performed to estimate unbound drug fractions in brain (f(u,brain)) and plasma (f(u,plasma)). This enabled estimation of unbound drug partitioning coefficients (K-p,K-uu,K-brain). The results indicated slight tendencies towards increase of total brain exposures in Pdgfb(ret/ret) mice as reflected in K-p,K-brain values, which were within the 2-fold limit. Part of these differences could be explained by differences in plasma protein binding. No difference was found in brain tissue binding. The combined in vivo and in vitro data resulted in no differences in BBB transport in pericyte-deficiency, as described by similar K-p,K-uu,K-brain Values in Pdgfb(ret/ret) and control mice. In conclusion, these findings imply no influence of pericytes on the extent of BBB transport of small-molecular drugs, and suggest preserved BBB features relevant for handling of this type of molecules irrespective of pericyte presence at the brain endothelium.

  • 41.
    Niaudet, Colin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Hofmann, Jennifer J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden..
    Mae, Maarja A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Jung, Bongnam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Gängel, Konstantin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Vanlandewijck, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Ekvarn, Elisabet
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden..
    Salvado, M. Dolores
    Karolinska Inst, Dept Med Biochem & Biophys, Physiol Chem 2, Stockholm, Sweden..
    Mehlem, Annika
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden..
    Al Sayegh, Sahar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    He, Liqun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Lebouvier, Thibaud
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Castro Freire, Marco
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Katayama, Kan
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden..
    Hultenby, Kjell
    Div Clin Res Ctr, Dept Lab Med, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Moessinger, Christine
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden..
    Tannenberg, Philip
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden.;Karolinska Inst, Dept Mol Med & Surg, Div Vasc Surg, Stockholm, Sweden..
    Cunha, Sara
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden..
    Pietras, Kristian
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden.;Lund Univ, Dept Lab Med, Lund, Sweden..
    Lavina Siemsen, Barbara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Hong, JongWook
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden..
    Berg, Tove
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Gpr116 Receptor Regulates Distinctive Functions in Pneumocytes and Vascular Endothelium2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 9, article id e0137949Article in journal (Refereed)
    Abstract [en]

    Despite its known expression in both the vascular endothelium and the lung epithelium, until recently the physiological role of the adhesion receptor Gpr116/ADGRF5 has remained elusive. We generated a new mouse model of constitutive Gpr116 inactivation, with a large genetic deletion encompassing exon 4 to exon 21 of the Gpr116 gene. This model allowed us to confirm recent results defining Gpr116 as necessary regulator of surfactant homeostasis. The loss of Gpr116 provokes an early accumulation of surfactant in the lungs, followed by a massive infiltration of macrophages, and eventually progresses into an emphysemalike pathology. Further analysis of this knockout model revealed cerebral vascular leakage, beginning at around 1.5 months of age. Additionally, endothelial-specific deletion of Gpr116 resulted in a significant increase of the brain vascular leakage. Mice devoid of Gpr116 developed an anatomically normal and largely functional vascular network, surprisingly exhibited an attenuated pathological retinal vascular response in a model of oxygen-induced retinopathy. These data suggest that Gpr116 modulates endothelial properties, a previously unappreciated function despite the pan-vascular expression of this receptor. Our results support the key pulmonary function of Gpr116 and describe a new role in the central nervous system vasculature.

  • 42.
    Rivera-Gonzalez, Guillermo C.
    et al.
    Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT 06520 USA..
    Shook, Brett A.
    Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT 06520 USA..
    Andrae, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Molecular Cell Biology.
    Holtrup, Brandon
    Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT 06520 USA..
    Bollag, Katherine
    Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT 06520 USA..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Rodeheffer, Matthew S.
    Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT 06520 USA.;Yale Univ, Sect Comparat Med, New Haven, CT 06520 USA..
    Horsley, Valerie
    Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT 06520 USA.;Yale Univ, Dept Dermatol, Yale Sch Med, New Haven, CT 06520 USA..
    Skin Adipocyte Stem Cell Self-Renewal Is Regulated by a PDGFA/AKT-Signaling Axis2016In: Cell Stem Cell, ISSN 1934-5909, E-ISSN 1875-9777, Vol. 19, no 6, p. 738-751Article in journal (Refereed)
    Abstract [en]

    Tissue growth and maintenance requires stem cell populations that self-renew, proliferate, and differentiate. Maintenance of white adipose tissue (WAT) requires the proliferation and differentiation of adipocyte stem cells (ASCs) to form postmitotic, lipid-filled mature adipocytes. Here we use the dynamic adipogenic program that occurs during hair growth to uncover an unrecognized regulator of ASC self-renewal and proliferation, PDGFA, which activates AKT signaling to drive and maintain the adipogenic program in the skin. Pdgfa expression is reduced in aged ASCs and is required for ASC proliferation and maintenance in the dermis, but not in other WATs. Our molecular and genetic studies uncover PI3K/AKT2 as a direct PDGFA target that is activated in ASCs during WAT hyperplasia and is functionally required for dermal ASC proliferation. Our data therefore reveal active mechanisms that regulate ASC self-renewal in the skin and show that distinct regulatory mechanisms operate in different WAT depots.

  • 43.
    Rodriguez, Patricia Q.
    et al.
    Karolinska Inst, Dept Med Biochem & Biophys, Div Matrix Biol, S-17177 Stockholm, Sweden.;Karolinska Univ, Huddinge Hosp, Karolinska Inst, KI AZ Integrated CardioMetab Ctr,Dept Med, Stockholm, Sweden..
    Oddsson, Asmundur
    Karolinska Inst, Dept Med Biochem & Biophys, Div Matrix Biol, S-17177 Stockholm, Sweden..
    Ebarasi, Lwaki
    Karolinska Univ, Huddinge Hosp, Karolinska Inst, KI AZ Integrated CardioMetab Ctr,Dept Med, Stockholm, Sweden..
    He, Bing
    Karolinska Inst, Dept Med Biochem & Biophys, Div Matrix Biol, S-17177 Stockholm, Sweden..
    Hultenby, Kjell
    Karolinska Inst, Dept Lab Med, Clin Res Ctr, S-17177 Stockholm, Sweden..
    Wernerson, Annika
    Dept Clin Sci Intervent & Technol, Div Renal Med, Stockholm, Sweden..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, S-17177 Stockholm, Sweden..
    Tryggvason, Karl
    Karolinska Inst, Dept Med Biochem & Biophys, Div Matrix Biol, S-17177 Stockholm, Sweden.;Duke NUS Grad Med Sch, Cardiovasc & Metab Disorders Program, Singapore, Singapore..
    Patrakka, Jaakko
    Karolinska Univ, Huddinge Hosp, Karolinska Inst, KI AZ Integrated CardioMetab Ctr,Dept Med, Stockholm, Sweden..
    Knockdown of Tmem234 in zebrafish results in proteinuria2015In: AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, ISSN 1931-857X, Vol. 309, no 11, p. F955-F966Article in journal (Refereed)
    Abstract [en]

    Podocytes are highly specialized epithelial cells located at the outer aspects of the glomerular capillary tuft and critical components of the kidney filtration barrier. To maintain their unique features, podocytes express a number of proteins that are only sparsely found elsewhere in the body. In this study, we have identified four (Tmem234, Znf185, Lrrc49, and Slfn5) new highly podocyte-enriched proteins. The proteins are strongly expressed by podocytes, while other parts of the kidney show only weak or no expression. Tmem234, Slfn5, and Lrrc49 are located in foot processes, whereas Znf185 is found in both foot and major processes. Expressional studies in developing kidneys show that these proteins are first expressed at the capillary stage glomerulus, the same stage when the formation of major and foot processes begins. We identified zebrafish orthologs for Tmem234 and Znf185 genes and knocked down their expression using morpholino technology. Studies in zebrafish larvae indicate that Tmem234 is essential for the organization and functional integrity of the pronephric glomerulus filtration barrier, as inactivation of Tmem234 expression results in foot process effacement and proteinuria. In summary, we have identified four novel highly podocyte - enriched proteins and show that one of them, Tmem234, is essential for the normal filtration barrier in the zebrafish pronephric glomerulus. Identification of new molecular components of the kidney filtration barrier opens up possibilities to study their role in glomerulus biology and diseases.

  • 44.
    Stanczuk, Lukas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Martinez-Corral, Ines
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Ulvmar, Maria H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Zhang, Yang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Laviña, Bàrbara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Fruttiger, Marcus
    Adams, Ralf H.
    Saur, Dieter
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Ortega, Sagrario
    Alitalo, Kari
    Graupera, Mariona
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    cKit Lineage Hemogenic Endothelium-Derived Cells Contribute to Mesenteric Lymphatic Vessels2015In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 10, no 10, p. 1708-1721Article in journal (Refereed)
    Abstract [en]

    Pathological lymphatic diseases mostly affect vessels in specific tissues, yet little is known about organ-specific regulation of the lymphatic vasculature. Here, we show that the vascular endothelial growth factor receptor 3 (VEGFR-3)/p110 alpha PI3-kinase signaling pathway is selectively required for the formation of mesenteric lymphatic vasculature. Using genetic lineage tracing, we demonstrate that part of the mesenteric lymphatic vasculature develops from cKit lineage cells of hemogenic endothelial origin through a process we define as lymphvasculogenesis. This is contrary to the current dogma that all mammalian lymphatic vessels form by sprouting from veins. Our results reveal vascular-bed-specific differences in the origin and mechanisms of vessel formation, which may critically underlie organ-specific manifestation of lymphatic dysfunction in disease. The progenitor cells identified in this study may be exploited to restore lymphatic function following cancer surgery, lymphedema, or tissue trauma.

  • 45.
    Tannenberg, P.
    et al.
    Karolinska Inst, Stockholm, Sweden..
    Folestad, E.
    Karolinska Inst, Stockholm, Sweden..
    Chang, Y. -T
    Gladh, H.
    Karolinska Inst, Stockholm, Sweden..
    Muhl, L.
    Karolinska Inst, Stockholm, Sweden..
    Laviña, Bàrbara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Genove, G.
    Karolinska Inst, Stockholm, Sweden..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Tran-Lundmark, K.
    Lund Univ, Lund, Sweden..
    Lack Of Pdgf-B Retention Ameliorates Hypoxia-Induced Pulmonary Hypertension2016In: American Journal of Respiratory and Critical Care Medicine, ISSN 1073-449X, E-ISSN 1535-4970, Vol. 193Article in journal (Refereed)
  • 46.
    Tannenberg, Philip
    et al.
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden;Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden.
    Chang, Ya-Ting
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden;Chang Gung Mem Hosp, Dept Pediat, Taoyuan, Taiwan.
    Muhl, Lars
    Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden.
    Laviña, Bàrbara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Gladh, Hanna
    Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden.
    Genove, Guillem
    Karolinska Inst, Dept Med, Integrated Cardio Metab Ctr, Huddinge, Sweden.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Dept Med, Integrated Cardio Metab Ctr, Huddinge, Sweden.
    Folestad, Erika
    Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden.
    Tran-Lundmark, Karin
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden;Lund Univ, Dept Expt Med Sci, Lund, Sweden.
    Extracellular retention of PDGF-B directs vascular remodeling in mouse hypoxia-induced pulmonary hypertension2018In: American Journal of Physiology - Lung cellular and Molecular Physiology, ISSN 1040-0605, E-ISSN 1522-1504, Vol. 314, no 4, p. 1593-1605Article in journal (Refereed)
    Abstract [en]

    Pulmonary hypertension (PH) is a lethal condition, and current vasodilator therapy has limited effect. Antiproliferative strategies targeting platelet-derived growth factor (PDGF) receptors, such as imatinib, have generated promising results in animal studies. Imatinib is, however, a nonspecific tyrosine kinase inhibitor and has in clinical studies caused unacceptable adverse events. Further studies are needed on the role of PDGF signaling in PH. Here, mice expressing a variant of PDGF-B with no retention motif (Pdgfb(ret/ret)), resulting in defective binding to extracellular matrix, were studied. Following 4 wk of hypoxia, right ventricular systolic pressure, right ventricular hypertrophy, and vascular remodeling were examined. Pdgfb(ret/ret) mice did not develop PH, as assessed by hemodynamic parameters. Hypoxia did, however, induce vascular remodeling in Pdgfb(ret/ret) mice; but unlike the situation in controls where the remodeling led to an increased concentric muscularization of arteries, the vascular remodeling in Pdgfb(ret/ret) mice was characterized by a diffuse muscularization, in which cells expressing smooth muscle cell markers were found in the interalveolar septa detached from the normally muscularized intra-acinar vessels. Additionally, fewer NG2-positive perivascular cells were found in Pdgfb(ret/ret) lungs, and mRNA analyses showed significantly increased levels of Il6 following hypoxia, a known promigratory factor for pericytes. No differences in proliferation were detected at 4 wk. This study emphasizes the importance of extracellular matrix-growth factor interactions and adds to previous knowledge of PDGF-B in PH pathobiology. In summary, Pdgfb(ret/ret) mice have unaltered hemodynamic parameters following chronic hypoxia, possibly secondary to a disorganized vascular muscularization.

  • 47.
    Tobin, Nicholas P.
    et al.
    Karolinska Inst, Dept Pathol & Oncol, S-17176 Stockholm, Sweden.;Univ Hosp, Canc Ctr Karolinska R8 3, Stockholm, Sweden..
    Wennmalm, Kristian
    Karolinska Inst, Dept Pathol & Oncol, S-17176 Stockholm, Sweden.;Univ Hosp, Canc Ctr Karolinska R8 3, Stockholm, Sweden..
    Lindstrom, Linda S.
    Univ Hosp, Canc Ctr Karolinska R8 3, Stockholm, Sweden.;Univ Calif San Francisco, Dept Surg, San Francisco, CA USA.;Karolinska Inst, Dept Biosci & Nutr, S-17176 Stockholm, Sweden..
    Foukakis, Theodoros
    Karolinska Inst, Dept Pathol & Oncol, S-17176 Stockholm, Sweden.;Univ Hosp, Canc Ctr Karolinska R8 3, Stockholm, Sweden..
    He, Liqun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Genove, Guillem
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, S-17176 Stockholm, Sweden..
    Ostman, Arne
    Karolinska Inst, Dept Pathol & Oncol, S-17176 Stockholm, Sweden.;Univ Hosp, Canc Ctr Karolinska R8 3, Stockholm, Sweden..
    Landberg, Goran
    Univ Gothenburg, Sahlgrenska Canc Ctr, Gothenburg, Sweden..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, S-17176 Stockholm, Sweden..
    Bergh, Jonas
    Karolinska Inst, Dept Pathol & Oncol, S-17176 Stockholm, Sweden.;Univ Hosp, Canc Ctr Karolinska R8 3, Stockholm, Sweden..
    An Endothelial Gene Signature Score Predicts Poor Outcome in Patients with Endocrine-Treated, Low Genomic Grade Breast Tumors2016In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 22, no 10, p. 2417-2426Article in journal (Refereed)
    Abstract [en]

    Purpose: The ability of vascular genes to provide treatment predictive information in breast cancer patients remains unclear. As such, we assessed the expression of genes representative of normal endothelial microvasculature (MV) in relation to treatment-specific patient subgroups. Experimental Design: We used expression data from 993 breast tumors to assess 57 MV genes (summarized to yield an MV score) as well as the genomic grade index (GGI) and PAM50 signatures. MV score was compared with CD31 staining by correlation and gene ontology (GO) analysis, along with clinicopathologic characteristics and PAM50 subtypes. Uni-, multivariate, and/or t-test analyses were performed in all and treatment-specific subgroups, along with a clinical trial cohort of patients with metastatic breast cancer, seven of whom received antiangiogenic therapy. Results: MV score did not correlate with microvessel density (correlation = 0.096), but displayed enrichment for angiogenic GO terms, and was lower in Luminal B tumors. In endocrine-treated patients, a high MV score was associated with decreased risk of metastasis [HR 0.58; 95% confidence interval (CI), 0.38-0.89], even after adjusting for histologic grade, but not GGI or PAM50. Subgroup analysis showed the prognostic strength of the MV score resided in low genomic grade tumors and MV score was significantly increased in metastatic breast tumors after treatment with sunitinib + docetaxel (P = 0.031). Conclusions: MV score identifies two groups of better and worse survival in low-risk endocrine-treated breast cancer patients. We also show normalization of tumor vasculature on a transcriptional level in response to an angiogenic inhibitor in human breast cancer samples.

  • 48.
    Vanlandewijck, Michael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, AstraZeneca Integrated Cardio Metab Ctr KI AZ ICM, Blickagangen 6, SE-14157 Huddinge, Sweden..
    He, Liqun
    Tianjin Med Univ, Key Lab Postneuroinjury Neurorepair & Regenerat C, Dept Neurosurg,Gen Hosp, Tianjin Neurol Inst,Minist Educ & Tianjin City, Tianjin 300052, Peoples R China..
    Mäe, Maarja Andaloussi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Andrae, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Ando, Koji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Del Gaudio, Francesca
    Karolinska Inst, Dept Cell & Mol Biol, Von Eulers Vag 3, SE-17177 Stockholm, Sweden..
    Nahar, Khayrun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Lebouvier, Thibaud
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Univ Lille, CHU,Memory Ctr, Distalz, Inserm,U1171, F-59000 Lille, France..
    Laviña, Bàrbara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Gouveia, Maria Leonor Seguardo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Sun, Ying
    Zhongyuan Union Genet Technol Co Ltd, Dept Bioinformat, Tianjin Airport Econ Area, 45 9th East Rd, Tianjin 300304, Peoples R China..
    Raschpergert, Elisabeth
    Karolinska Inst, AstraZeneca Integrated Cardio Metab Ctr KI AZ ICM, Blickagangen 6, SE-14157 Huddinge, Sweden..
    Räsänen, Markus
    Univ Helsinki, Wihuri Res Inst, Haartmaninkatu 8,POB 63, FI-00014 Helsinki, Finland.;Univ Helsinki, Translat Canc Biol Program, Biomedicum Helsinki, Haartmaninkatu 8,POB 63, FI-00014 Helsinki, Finland..
    Zarb, Yvette
    Zurich Univ, Univ Zurich Hosp, Div Neurosurg, CH-8091 Zurich, Switzerland..
    Mochizuki, Naoki
    Natl Cerebral & Cardiovasc Ctr, Dept Cell Biol, Res Inst, Suita, Osaka, Japan.;Natl Cerebral & Cardiovasc Ctr, AMED CREST, Suita, Osaka, Japan..
    Keller, Annika
    Zurich Univ, Univ Zurich Hosp, Div Neurosurg, CH-8091 Zurich, Switzerland..
    Lendahl, Urban
    Karolinska Inst, Dept Cell & Mol Biol, Von Eulers Vag 3, SE-17177 Stockholm, Sweden..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, AstraZeneca Integrated Cardio Metab Ctr KI AZ ICM, Blickagangen 6, SE-14157 Huddinge, Sweden.
    A molecular atlas of cell types and zonation in the brain vasculature2018In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 554, no 7693, p. 475-480Article in journal (Refereed)
    Abstract [en]

    Cerebrovascular disease is the third most common cause of death in developed countries, but our understanding of the cells that compose the cerebral vasculature is limited. Here, using vascular single-cell transcriptomics, we provide molecular definitions for the principal types of blood vascular and vessel-associated cells in the adult mouse brain. We uncover the transcriptional basis of the gradual phenotypic change (zonation) along the arteriovenous axis and reveal unexpected cell type differences: a seamless continuum for endothelial cells versus a punctuated continuum for mural cells. We also provide insight into pericyte organotypicity and define a population of perivascular fibroblast-like cells that are present on all vessel types except capillaries. Our work illustrates the power of single-cell transcriptomics to decode the higher organizational principles of a tissue and may provide the initial chapter in a molecular encyclopaedia of the mammalian vasculature.

  • 49.
    Vanlandewijck, Michael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Novum, ICMC, SE-14157 Stockholm, Sweden..
    Lebouvier, Thibaud
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Mae, Maarja Andaloussi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Nahar, Khayrun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Hornemann, Simone
    Univ Zurich, Univ Zurich Hosp, Inst Neuropathol, CH-8091 Zurich, Switzerland..
    Kenkel, David
    Univ Zurich, Univ Zurich Hosp, Inst Diagnost & Intervent Radiol, CH-8091 Zurich, Switzerland..
    Cunha, Sara I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lennartsson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Boss, Andreas
    Univ Zurich, Univ Zurich Hosp, Inst Diagnost & Intervent Radiol, CH-8091 Zurich, Switzerland..
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Keller, Annika
    Univ Zurich, Univ Zurich Hosp, Div Neurosurg, CH-8091 Zurich, Switzerland..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Functional Characterization of Germline Mutations in PDGFB and PDGFRB in Primary Familial Brain Calcification2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 11, article id e0143407Article in journal (Refereed)
    Abstract [en]

    Primary Familial Brain Calcification (PFBC), a neurodegenerative disease characterized by progressive pericapillary calcifications, has recently been linked to heterozygous mutations in PDGFB and PDGFRB genes. Here, we functionally analyzed several of these mutations in vitro. All six analyzed PDGFB mutations led to complete loss of PDGF-B function either through abolished protein synthesis or through defective binding and/or stimulation of PDGF-R beta. The three analyzed PDGFRB mutations had more diverse consequences. Whereas PDGF-R beta autophosphorylation was almost totally abolished in the PDGFRB L658P mutation, the two sporadic PDGFRB mutations R987W and E1071V caused reductions in protein levels and specific changes in the intensity and kinetics of PLC. activation, respectively. Since at least some of the PDGFB mutations were predicted to act through haploinsufficiency, we explored the consequences of reduced Pdgfb or Pdgfrb transcript and protein levels in mice. Heterozygous Pdgfb or Pdgfrb knockouts, as well as double Pdgfb(+/-); Pdgfrb(+/-) mice did not develop brain calcification, nor did Pdgfrb(redeye/redeye) mice, which show a 90% reduction of PDGFR beta protein levels. In contrast, Pdgfb(ret/ret) mice, which have altered tissue distribution of PDGF-B protein due to loss of a proteoglycan binding motif, developed brain calcifications. We also determined pericyte coverage in calcification-prone and non-calcification-prone brain regions in Pdgfb(ret/ret) mice. Surprisingly and contrary to our hypothesis, we found that the calcification-prone brain regions in Pdgfb(ret/ret) mice model had a higher pericyte coverage and a more intact blood-brain barrier (BBB) compared to non-calcification-prone brain regions. While our findings provide clear evidence that loss-of-function mutations in PDGFB or PDGFRB cause PFBC, they also demonstrate species differences in the threshold levels of PDGF-B/PDGF-R beta signaling that protect against small-vessel calcification in the brain. They further implicate region-specific susceptibility factor(s) in PFBC pathogenesis that are distinct from pericyte and BBB deficiency.

  • 50.
    Villasenor, Roberto
    et al.
    Roche Innovat Ctr Basel, Roche Pharma Res & Early Dev pRED, Neurodegenerat & Regenerat, Basel, Switzerland..
    Ozmen, Laurence
    Roche Innovat Ctr Basel, Roche Pharma Res & Early Dev pRED, Neurodegenerat & Regenerat, Basel, Switzerland..
    Messaddeq, Nadia
    UdS, Coll France, CNRS, IGBMC,INSERM,ICS, BP 10142, Strasbourg, France..
    Gruninger, Fiona
    Roche Innovat Ctr Basel, Roche Pharma Res & Early Dev pRED, Neurodegenerat & Regenerat, Basel, Switzerland..
    Loetscher, Hansruedi
    Roche Innovat Ctr Basel, Roche Pharma Res & Early Dev pRED, Neurodegenerat & Regenerat, Basel, Switzerland..
    Keller, Annika
    Univ Zurich, Univ Zurich Hosp, Div Neurosurg, Frauenklin Str 10, CH-8091 Zurich, Switzerland..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden..
    Freskgard, Per-Ola
    Roche Innovat Ctr Basel, Roche Pharma Res & Early Dev pRED, Neurodegenerat & Regenerat, Basel, Switzerland..
    Collin, Ludovic
    Roche Innovat Ctr Basel, Roche Pharma Res & Early Dev pRED, Neurodegenerat & Regenerat, Basel, Switzerland..
    Trafficking of Endogenous Immunoglobulins by Endothelial Cells at the Blood-Brain Barrier2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 25658Article in journal (Refereed)
    Abstract [en]

    The Blood-Brain Barrier (BBB) restricts access of large molecules to the brain. The low endocytic activity of brain endothelial cells (BECs) is believed to limit delivery of immunoglobulins (IgG) to the brain parenchyma. Here, we report that endogenous mouse IgG are localized within intracellular vesicles at steady state in BECs in vivo. Using high-resolution quantitative microscopy, we found a fraction of endocytosed IgG in lysosomes. We observed that loss of pericytes (key components of the BBB) in pdgf-b(ret/ret) mice affects the intracellular distribution of endogenous mouse IgG in BECs. In these mice, endogenous IgG was not detected within lysosomes but instead accumulate at the basement membrane and brain parenchyma. Such IgG accumulation could be due to reduced lysosomal clearance and increased sorting to the abluminal membrane of BECs. Our results suggest that, in addition to low uptake from circulation, IgG lysosomal degradation may be a downstream mechanism by which BECs further restrict IgG access to the brain.

12 1 - 50 of 56
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