CdGAP/ARHGAP31, a Cdc42/Rac1 GTPase regulator, is critical for vascular development and VEGF-mediated angiogenesis.
CdGAP/ARHGAP31, a Cdc42/Rac1 GTPase regulator, is critical for vascular development and VEGF-mediated angiogenesis.
复制标题
CDGAP/ARHGAP31是CDC42/RAC1 GTPase调节剂，对于血管发育和VEGF介导的血管生成至关重要。
DOI：
10.1038/srep27485
复制
发表时间：
2016-06-07
影响因子：
4.6
通讯作者：
Royal I
中科院分区：
文献类型：
--
作者：
Caron C;DeGeer J;Fournier P;Duquette PM;Luangrath V;Ishii H;Karimzadeh F;Lamarche-Vane N;Royal I
CdGAP/ARHGAP31基因编码gtpase激活蛋白Rac1和Cdc42，据报道，该基因突变可导致亚当斯-奥利弗发育综合征（Adams-Oliver developmental syndrome），通常与血管缺陷相关。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尚不清楚。在这里，我们发现cdgap缺陷小鼠胚胎在E15.5时血管发育受损。这与浅表血管缺损和皮下水肿有关，导致44%的胚胎/围产期死亡率。在CdGAP−/−小鼠中，vegf驱动的血管生成存在缺陷，显示主动脉环外植体的毛细血管发芽减少。同样，vegf依赖性内皮细胞迁移和毛细血管形成在CdGAP敲低后受到抑制。在机制上，CdGAP与VEGF受体-2相关并控制VEGF依赖性信号传导。因此，CdGAP耗损会导致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降低。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，并强调了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。
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.