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Disruption of the Extracellular Matrix Progressively Impairs Central Nervous System Vascular Maturation Downstream of beta-Catenin Signaling
Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
Karolinska Inst, Sweden; Ludwig Inst Canc Res Ltd, Sweden.
Karolinska Inst, Sweden; Ludwig Inst Canc Res Ltd, Sweden.
Univ Libre Bruxelles, Belgium.
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2019 (English)In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 39, no 7, p. 1432-1447Article in journal (Refereed) Published
Abstract [en]

Objective- The Wnt/beta-catenin pathway orchestrates development of the blood-brain barrier, but the downstream mechanisms involved at different developmental windows and in different central nervous system (CNS) tissues have remained elusive. Approach and Results- Here, we create a new mouse model allowing spatiotemporal investigations of Wnt/beta-catenin signaling by induced overexpression of Axin1, an inhibitor of beta-catenin signaling, specifically in endothelial cells (Axin1(iEC)-(OE)). AOE (Axin1 overexpression) in Axin1(iEC)-(OE) mice at stages following the initial vascular invasion of the CNS did not impair angiogenesis but led to premature vascular regression followed by progressive dilation and inhibition of vascular maturation resulting in forebrain-specific hemorrhage 4 days post-AOE. Analysis of the temporal Wnt/beta-catenin driven CNS vascular development in zebrafish also suggested that Axin1(iEC)-(OE) led to CNS vascular regression and impaired maturation but not inhibition of ongoing angiogenesis within the CNS. Transcriptomic profiling of isolated, beta-catenin signaling-deficient endothelial cells during early blood-brain barrier-development (E11.5) revealed ECM (extracellular matrix) proteins as one of the most severely deregulated clusters. Among the 20 genes constituting the forebrain endothelial cell-specific response signature, 8 (Adamtsl2, Apod, Ctsw, Htra3, Pglyrp1, Spock2, Ttyh2, and Wfdc1) encoded bona fide ECM proteins. This specific beta-catenin-responsive ECM signature was also repressed in Axin1(iEC)-(OE) and endothelial cell-specific beta-catenin-knockout mice (Ctnnb1-KOiEC) during initial blood-brain barrier maturation (E14.5), consistent with an important role of Wnt/beta-catenin signaling in orchestrating the development of the forebrain vascular ECM. Conclusions- These results suggest a novel mechanism of establishing a CNS endothelium-specific ECM signature downstream of Wnt-beta-catenin that impact spatiotemporally on blood-brain barrier differentiation during forebrain vessel development.

Place, publisher, year, edition, pages
LIPPINCOTT WILLIAMS & WILKINS , 2019. Vol. 39, no 7, p. 1432-1447
Keywords [en]
basement membrane; blood-brain barrier; central nervous system; embryonic development; endothelial cells; extracellular matrix; vasculature
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-158947DOI: 10.1161/ATVBAHA.119.312388ISI: 000472969200018PubMedID: 31242033OAI: oai:DiVA.org:liu-158947DiVA, id: diva2:1338183
Note

Funding Agencies|Cancerfonden [CAN 2010/679]; Karolinska Funding for Doctorial Studies; Swedish Society for Medical Research; Jeanssons Stiftelser; Swedish Research Council; H2020-MSCA-RISE (3D-NEONET); Johnson Johnson [K240001043]; Marie Curie FP7 people initiative Fellowship [626544]; National Institutes of Health [AR070748, AR53890]; Swedish Brain Foundation; Tore Nilsons Stiftelse; Tornspiran; Lars Hiertas Stiftelse; Jane Foundation; Dan Olsson Foundation; Samariten and Bergvalls Stiftelse

Available from: 2019-07-20 Created: 2019-07-20 Last updated: 2019-11-12

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