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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.

Author information

1
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.
2
IFOM-The FIRC Institute of Molecular Oncology, Milan, Italy (M.C., E.D.).
3
Department of Pharmacology and Physiology (J.K.), Karolinska Institutet, Stockholm, Sweden.
4
Department of Immunology, Genetics and Pathology, University of Uppsala, Sweden (E.D.).

Abstract

OBJECTIVE:

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.

CONCLUSIONS:

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.

KEYWORDS:

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

PMID:
31533473
DOI:
10.1161/ATVBAHA.119.312749

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