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

Abstract

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.

Autocrine VEGF and IL-8 Promote Migration via Src/Vav2/Rac1/PAK1 Signaling in Human Umbilical Vein Endothelial Cells

“…It has been reported that IL-8 promotes endothelial cell migration by increasing the activity of Rac1 [22]. Caron et al have shown that activation of Rac1 mediates VEGF-stimulated endothelial cell migration [41]. Our results found that when Rac1 activation was blocked, autocrine VEGF and IL-8-stimulated cell migration was dramatically diminished.…”

Current opinion in the molecular genetics of Adams-Oliver syndrome

“…[20,22] More recently, analysis of a knock-out mouse model has highlighted a critical role for Arhgap31 in vascular development and VEGF-mediated angiogenesis, providing a novel molecular link between Rho GTPase dysregulation and vascular development in this disorder. [23] These findings further support the hypothesis that AOS represents a constellation of clinical features resulting from an early embryonic vascular abnormality. [24] ARHGAP31 mutant transcripts are stable and have been demonstrated to lead to constitutive inactivation of Cdc42 through a gain-of-function mechanism, potentially due to protein truncation impeding regulation of the RhoGAP domain.…”

Weighted Single-Step Genome-Wide Association Study for Growth Traits in Chinese Simmental Beef Cattle

“…The most important window, BTA1: 64788160-64867718 bp, contributed to 3.44% of the genetic variance of 18MW and was located within gene Rho GTPase activating protein 31 (ARHGAP31). ARHGAP31 encodes a GTPase-activating protein (GAP) and plays a role in regulating the cellular processes of cycling between an inactive GDP-bound and active GTP-bound conformation [36]. GAP has been reported to have functions in protein trafficking and cell growth and serves as a molecular switch involved in the regulation of various cytoskeleton-related events and gene transcription [37].…”