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Arterioscler Thromb Vasc Biol. 2019 Nov;39(11):2273-2288. doi: 10.1161/ATVBAHA.119.312749. Epub 2019 Sep 19.

Endothelial β-Catenin Signaling Supports Postnatal Brain and Retinal Angiogenesis by Promoting Sprouting, Tip Cell Formation, and VEGFR (Vascular Endothelial Growth Factor Receptor) 2 Expression.

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From the Division of Vascular Biology, Department of Medical Biochemistry and Biophysics (A.M., M.T., N.J., J.W.-K., F.C.N., D.N.), Karolinska Institutet, Stockholm, Sweden.
IFOM-The FIRC Institute of Molecular Oncology, Milan, Italy (M.C., E.D.).
Department of Pharmacology and Physiology (J.K.), Karolinska Institutet, Stockholm, Sweden.
Department of Immunology, Genetics and Pathology, University of Uppsala, Sweden (E.D.).



Activation of endothelial β-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/β-catenin pathway contribute to inherited blinding disorders because of defective vascular development and dysfunctional blood-retina barrier. Despite a vital role for endothelial β-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 β-catenin signaling caused hypovascularization of the postnatal retina and brain because of deficient endothelial cell proliferation and sprouting. Mosaic genetic analysis demonstrated that endothelial β-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 β-catenin. Importantly, impaired endothelial β-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.


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


beta catenin; blood-brain barrier; central nervous system; endothelial cell; vegf


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