CdGAP/ARHGAP31, a Cdc42/Rac1 GTPase regulator, is critical for vascular development and VEGF-mediated angiogenesis.
Mutations in the CdGAP/ARHGAP31 gene, which encodes a GTPase-activating protein for Rac1 and Cdc42, have been reported causative in the Adams-Oliver developmental syndrome often associated with vascular defects. However, despite its abundant expression in endothelial cells, CdGAP function in the vasculature remains unknown. Here, we show that vascular development is impaired in CdGAP-deficient mouse embryos at E15.5. This is associated with superficial vessel defects and subcutaneous edema, resulting in 44% embryonic/perinatal lethality. VEGF-driven angiogenesis is defective in CdGAP(-/-) mice, showing reduced capillary sprouting from aortic ring explants. Similarly, VEGF-dependent endothelial cell migration and capillary formation are inhibited upon CdGAP knockdown. Mechanistically, CdGAP associates with VEGF receptor-2 and controls VEGF-dependent signaling. Consequently, CdGAP depletion results in impaired VEGF-mediated Rac1 activation and reduced phosphorylation of critical intracellular mediators including Gab1, Akt, PLCγ and SHP2. These findings are the first to demonstrate the importance of CdGAP in embryonic vascular development and VEGF-induced signaling, and highlight CdGAP as a potential therapeutic target to treat pathological angiogenesis and vascular dysfunction.
CRCHUM - Centre de recherche du Centre Hospitalier de l'Université de Montréal and Institut du Cancer de Montréal, Montréal, Québec, Canada.
Christine
C
Caron
Cancer Research Program, Research Institute-McGill University Hospital Centre, Montreal, Quebec, Canada.|Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada.
Jonathan
J
DeGeer
CRCHUM - Centre de recherche du Centre Hospitalier de l'Université de Montréal and Institut du Cancer de Montréal, Montréal, Québec, Canada.
Patrick
P
Fournier
Cancer Research Program, Research Institute-McGill University Hospital Centre, Montreal, Quebec, Canada.|Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada.
Philippe M
PM
Duquette
Cancer Research Program, Research Institute-McGill University Hospital Centre, Montreal, Quebec, Canada.|Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada.
Vilayphone
V
Luangrath
Cancer Research Program, Research Institute-McGill University Hospital Centre, Montreal, Quebec, Canada.|Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada.
Hidetaka
H
Ishii
Cancer Research Program, Research Institute-McGill University Hospital Centre, Montreal, Quebec, Canada.|Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada.
Fereshteh
F
Karimzadeh
Cancer Research Program, Research Institute-McGill University Hospital Centre, Montreal, Quebec, Canada.|Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada.
Nathalie
N
Lamarche-Vane
CRCHUM - Centre de recherche du Centre Hospitalier de l'Université de Montréal and Institut du Cancer de Montréal, Montréal, Québec, Canada.|Department of Medicine, Université de Montréal, Montréal, Québec, Canada.
Isabelle
I
Royal
D000818:Animals; D001808:Blood Vessels / Q000196:embryology*; D020690:GTPase-Activating Proteins / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*; D020764:cdc42 GTP-Binding Protein / Q000502:physiology*
C115491:Arhgap31 protein, mouse; D020690:GTPase-Activating Proteins; D042461:Vascular Endothelial Growth Factor A; D020764:cdc42 GTP-Binding Protein