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Endothelial beta-Catenin Signaling Supports Postnatal Brain and Retinal Angiogenesis by Promoting Sprouting, Tip Cell Formation, and VEGFR (Vascular Endothelial Growth Factor Receptor) 2 Expression
Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Biomedicum 6D, S-17165 Stockholm, Sweden.
Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Biomedicum 6D, S-17165 Stockholm, Sweden.
Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Biomedicum 6D, S-17165 Stockholm, Sweden.
Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Biomedicum 6D, S-17165 Stockholm, Sweden.
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2019 (English)In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 39, no 11, p. 2273-2288Article in journal (Refereed) Published
Abstract [en]

Objective: Activation of endothelial beta-catenin signaling by neural cell-derived Norrin or Wnt ligands is vital for the vascularization of the retina and brain. Mutations in members of the Norrin/beta-catenin pathway contribute to inherited blinding disorders because of defective vascular development and dysfunctional blood-retina barrier. Despite a vital role for endothelial beta-catenin signaling in central nervous system health and disease, its contribution to central nervous system angiogenesis and its interactions with downstream signaling cascades remains incompletely understood.

Approach and Results: Here, using genetically modified mouse models, we show that impaired endothelial beta-catenin signaling caused hypovascularization of the postnatal retina and brain because of deficient endothelial cell proliferation and sprouting. Mosaic genetic analysis demonstrated that endothelial beta-catenin promotes but is not required for tip cell formation. In addition, pharmacological treatment revealed that angiogenesis under conditions of inhibited Notch signaling depends upon endothelial beta-catenin. Importantly, impaired endothelial beta-catenin signaling abrogated the expression of the VEGFR (vascular endothelial growth factor receptor)-2 and VEGFR3 in brain microvessels but not in the lung endothelium.

Conclusions: Our study identifies molecular crosstalk between the Wnt/beta-catenin and the Notch and VEGF-A signaling pathways and strongly suggest that endothelial beta-catenin signaling supports central nervous system angiogenesis by promoting endothelial cell sprouting, tip cell formation, and VEGF-A/VEGFR2 signaling.

Place, publisher, year, edition, pages
LIPPINCOTT WILLIAMS & WILKINS , 2019. Vol. 39, no 11, p. 2273-2288
Keywords [en]
beta catenin, blood-brain barrier, central nervous system, endothelial cell, vegf
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-397792DOI: 10.1161/ATVBAHA.119.312749ISI: 000494483700015PubMedID: 31533473OAI: oai:DiVA.org:uu-397792DiVA, id: diva2:1373417
Funder
Swedish Research Council, 201303950Swedish Cancer SocietyMagnus Bergvall FoundationĂ…ke Wiberg FoundationKnut and Alice Wallenberg FoundationEU, European Research Council, 742922Available from: 2019-11-27 Created: 2019-11-27 Last updated: 2019-11-27Bibliographically approved

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Dejana, Elisabetta

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