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Regulation of VEGFR2 signaling in angiogenesis and vascular permeability
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. (Lena Claesson-Welsh and Mats Hellström)
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Angiogenesis and vascular permeability occur in physiological and pathological conditions. Angiogenesis denotes the process of blood vessel formation from preexisting quiescent vessels. Angiogenesis is initiated by proangiogenic factors, inducing endothelial cell sprouting, migration and anastomosis, followed by regression of the new vessels or maturation into a quiescent status. Vascular permeability is the process where blood vessels exchange nutrients, solutes and inflammatory cells with the surrounding tissue. Small molecules freely cross the endothelial wall, however macromolecules and cells leak out from the vasculature only after stimulation by certain factors, including VEGF. Angiogenesis and vascular permeability are tightly regulated physiological processes, but uncontrolled angiogenesis and excessive leakage lead to pathological conditions and the progression of several diseases.

VEGF and its receptor VEGFR2 are critical players in angiogenesis and in vascular permeability. The binding of the ligand to the receptor is not the only event involved in the activation and regulation of the signaling cascade. Coreceptors, kinases, phosphatases, and other proteins involved in the trafficking of the complex modulate the signal amplitude and duration.

VEGF/VEGFR2 complex combined with the coreceptor NRP1 has a strong pro-angiogenic action and a critical role in angiogenesis. Both VEGFR2 and NRP1 bind VEGF and can present VEGF in cis, when both VEGFR2 and NRP1 are expressed on the same endothelial cell or in trans, when NRP1 is expressed on an adjacent endothelial cell or another type of cell.

Y949 and Y1212 are two of the main phosphorylation sites of VEGFR2 induced by VEGFA. The binding of phosphorylated Y949 to the SH2 domain of TSAd regulates vascular permeability leading to Src activation and adherens junction opening in vitro. Phospho-Y1212 is implicated in actin stress fiber remodeling via the adapter Nck, affecting the actin cytoskeleton and endothelial cell migration in vitro.

Paladin is a vascular-enriched phosphatase-domain containing protein without reported phosphatase activity and is a negative regulator of insulin receptor and Toll-like receptor 9 signaling.

In this thesis work, I have investigated the spatial dynamics of NRP1/VEGFR2 complex formation (in cis and in trans) for coordinating VEGF-mediated angiogenesis in physiological and in pathological conditions (Paper I). I have studied, in vivo, the role of VEGFR2 Y949 in vascular permeability and metastatic spread (Paper II) and the role of VEGFR2 Y1212 in angiogenic remodeling and vessel stability (Paper III). Furthermore, I have examined paladin’s role in regulating VEGF/VEGFR2 signaling and VE-cadherin junction stability, in angiogenic sprouting and vascular permeability (Paper IV).

In conclusion, VEGF/VEGFR2 signaling is regulated by a multifactor system and each individual regulatory mechanism leads to a specific outcome in angiogenesis, vascular permeability and vessel stability.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. , 56 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1240
Keyword [en]
VEGFR2, angiogenesis, permeability, NRP1, Y949, Y1212, paladin
National Category
Cell and Molecular Biology Cardiac and Cardiovascular Systems Cancer and Oncology
Research subject
Molecular Medicine
Identifiers
URN: urn:nbn:se:uu:diva-300084ISBN: 978-91-554-9637-1OAI: oai:DiVA.org:uu-300084DiVA: diva2:951031
Public defence
2016-09-29, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2016-09-02 Created: 2016-08-02 Last updated: 2016-09-05
List of papers
1. NRP1 Presented in trans to the Endothelium Arrests VEGFR2 Endocytosis, Preventing Angiogenic Signaling and Tumor Initiation
Open this publication in new window or tab >>NRP1 Presented in trans to the Endothelium Arrests VEGFR2 Endocytosis, Preventing Angiogenic Signaling and Tumor Initiation
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2014 (English)In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 28, no 6, 633-646 p.Article in journal (Refereed) Published
Abstract [en]

Neuropilin 1 (NRP1) modulates angiogenesis by binding vascular endothelial growth factor (VEGF) and its receptor, VEGFR2. We examined the consequences when VEGFR2 and NRP1 were expressed on the same cell (cis) or on different cells (trans). In cis, VEGF induced rapid VEGFR2/NRP1 complex formation and internalization. In trans, complex formation was delayed and phosphorylation of phospholipase C gamma (PLC gamma) and extracellular regulated kinase 2 (ERK2) was prolonged, whereas ERK1 phosphorylation was reduced. Trans complex formation suppressed initiation and vascularization of NRP1-expressing mouse fibrosarcoma and melanoma. Suppression in trans required high-affinity, steady-state binding of VEGF to NRP1, which was dependent on the NRP1 C-terminal domain. Compatible with a trans effect of NRP1, quiescent vasculature in the developing retina showed continuous high NRP1 expression, whereas angiogenic sprouting occurred where NRP1 levels fluctuated between adjacent endothelial cells. Therefore, through communication in trans, NRP1 can modulate VEGFR2 signaling and suppress angiogenesis.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-224353 (URN)10.1016/j.devcel.2014.02.010 (DOI)000333765900005 ()
Available from: 2014-05-13 Created: 2014-05-09 Last updated: 2016-08-26Bibliographically approved
2. VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread
Open this publication in new window or tab >>VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread
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2016 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, 11017Article in journal (Refereed) Published
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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-288617 (URN)10.1038/ncomms11017 (DOI)000372721400001 ()27005951 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research CouncilKnut and Alice Wallenberg FoundationEU, European Research Council, 294556 BBBARRIERWenner-Gren Foundations
Available from: 2016-05-11 Created: 2016-04-28 Last updated: 2016-08-26Bibliographically approved
3. VEGFR2 pY1212 signaling regulates endothelial cell proliferation and vessel stability
Open this publication in new window or tab >>VEGFR2 pY1212 signaling regulates endothelial cell proliferation and vessel stability
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(English)Manuscript (preprint) (Other academic)
National Category
Cancer and Oncology Cell and Molecular Biology Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-300081 (URN)
Available from: 2016-08-02 Created: 2016-08-02 Last updated: 2016-08-26
4. Paladin (Pald1) regulates endothelial sprouting, VE-cadherin junction stability and vascular permeability
Open this publication in new window or tab >>Paladin (Pald1) regulates endothelial sprouting, VE-cadherin junction stability and vascular permeability
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(English)Manuscript (preprint) (Other academic)
National Category
Cell and Molecular Biology Cardiac and Cardiovascular Systems Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-300083 (URN)
Available from: 2016-08-02 Created: 2016-08-02 Last updated: 2016-08-26

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