CdGAP/ARHGAP31, a Cdc42/Rac1 GTPase regulator, is critical for vascular development and VEGF-mediated angiogenesis

被引:26
作者
Caron, Christine [1 ,2 ]
DeGeer, Jonathan [3 ,4 ]
Fournier, Patrick [1 ,2 ]
Duquette, Philippe M. [3 ,4 ]
Luangrath, Vilayphone [3 ,4 ]
Ishii, Hidetaka [3 ,4 ]
Karimzadeh, Fereshteh [3 ,4 ]
Lamarche-Vane, Nathalie [3 ,4 ]
Royal, Isabelle [1 ,2 ,5 ]
机构
[1] CRCHUM, Montreal, PQ, Canada
[2] Inst Canc Montreal, Montreal, PQ, Canada
[3] McGill Univ, Ctr Hosp, Canc Res Program, Res Inst, Montreal, PQ, Canada
[4] McGill Univ, Dept Anat & Cell Biol, Montreal, PQ, Canada
[5] Univ Montreal, Dept Med, Montreal, PQ H3C 3J7, Canada
基金
加拿大健康研究院;
关键词
ADAMS-OLIVER SYNDROME; OF-FUNCTION MUTATIONS; GROWTH-FACTOR; ACTIVATING PROTEIN; CELL-MIGRATION; CDGAP; GAB1; KINASE; APLASIA; DOCK6;
D O I
10.1038/srep27485
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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, PLC gamma 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.
引用
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页数:10
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