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

Christine Caron¹, Jonathan DeGeer^2,3, Patrick Fournier¹

¹CRCHUM - Centre de recherche du Centre Hospitalier de l'Université de Montréal and Institut du Cancer de Montréal, Montréal, Québec, Canada.

Scientific Reports

|June 9, 2016

Insights

CdGAP (cytoskeleton-associated Rho GTPase-activating protein) is crucial for embryonic vascular development. Its deficiency impairs blood vessel formation by disrupting VEGF signaling, leading to developmental defects and lethality.

Area of Science:

Molecular Biology
Developmental Biology
Cell Biology

Background:

Mutations in the CdGAP/ARHGAP31 gene are linked to Adams-Oliver syndrome, often involving vascular defects.
CdGAP is highly expressed in endothelial cells, but its role in vascular development was previously unknown.

Purpose of the Study:

To investigate the function of CdGAP in embryonic vascular development and its role in VEGF-mediated signaling.

Main Methods:

Utilized CdGAP-deficient mouse models (CdGAP-/-) and CdGAP knockdown in endothelial cells.
Assessed embryonic vascular development at E15.5, including vessel morphology and subcutaneous edema.
Examined VEGF-driven angiogenesis using aortic ring explants and endothelial cell migration assays.
Investigated the molecular mechanism by analyzing CdGAP interaction with VEGF receptor-2 and downstream signaling pathways (Rac1 activation, phosphorylation of Gab1, Akt, PLCγ, SHP2).

Main Results:

CdGAP deficiency in mice led to impaired vascular development, superficial vessel defects, subcutaneous edema, and 44% embryonic/perinatal lethality.
VEGF-driven angiogenesis, capillary sprouting, endothelial cell migration, and capillary formation were significantly reduced in CdGAP-deficient embryos and knockdown models.
CdGAP was found to associate with VEGF receptor-2, modulating VEGF-dependent signaling pathways.
CdGAP depletion resulted in impaired VEGF-mediated Rac1 activation and reduced phosphorylation of key signaling intermediates.

Conclusions:

CdGAP plays a critical role in embryonic vascular development and is essential for proper VEGF-induced signaling.
CdGAP acts as a key regulator of endothelial cell function in response to VEGF.
CdGAP represents a potential therapeutic target for pathological angiogenesis and vascular dysfunction.

Read full analysis

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.

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