期刊
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
卷 39, 期 11, 页码 2273-2288出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.119.312749
关键词
beta catenin; blood-brain barrier; central nervous system; endothelial cell; vegf
资金
- Swedish Research Council [201303950]
- Swedish Cancer Society
- Karolinska Institute
- Magnus Bergvalls Stiftelse
- Jeanssons Stiftelser
- Ake Wibergs Stiftelse
- Ahlen-stiftelsen
- Ogonfonden
- Swedish Science Council
- Knut and Alice Wallenberg Foundation
- European Research Council (project EC-ERC-VEPC) [742922]
- Italian Association for Cancer Research [AIRC IG 18683]
- AIRC 5x1000 call MYNERVA projects
- European Research Council (ERC) [742922] Funding Source: European Research Council (ERC)
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.
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