Caron Christine, DeGeer Jonathan, Fournier Patrick, Duquette Philippe M, Luangrath Vilayphone, Ishii Hidetaka, Karimzadeh Fereshteh, Lamarche-Vane Nathalie, Royal Isabelle
CRCHUM - Centre de recherche du Centre Hospitalier de l'Université de Montréal and Institut du Cancer de Montréal, Montréal, Québec, Canada.
Cancer Research Program, Research Institute-McGill University Hospital Centre, Montreal, Quebec, Canada.
Sci Rep. 2016 Jun 7;6:27485. doi: 10.1038/srep27485.
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.
CdGAP/ARHGAP31基因编码一种针对Rac1和Cdc42的GTP酶激活蛋白，该基因的突变已被报道是常与血管缺陷相关的亚当斯-奥利弗发育综合征的病因。然而，尽管CdGAP在内皮细胞中大量表达，但其在脉管系统中的功能仍不清楚。在此，我们表明在E15.5时，CdGAP缺陷型小鼠胚胎的血管发育受损。这与浅表血管缺陷和皮下水肿有关，导致44%的胚胎/围产期致死率。VEGF驱动的血管生成在CdGAP(-/-)小鼠中存在缺陷，表现为主动脉环外植体的毛细血管芽生减少。同样，CdGAP敲低后，VEGF依赖的内皮细胞迁移和毛细血管形成受到抑制。从机制上讲，CdGAP与VEGF受体-2结合并控制VEGF依赖的信号传导。因此，CdGAP的缺失导致VEGF介导的Rac1激活受损，以及包括Gab1、Akt、PLCγ和SHP2在内的关键细胞内介质的磷酸化减少。这些发现首次证明了CdGAP在胚胎血管发育和VEGF诱导的信号传导中的重要性，并突出了CdGAP作为治疗病理性血管生成和血管功能障碍的潜在治疗靶点。
