The Rho protein exchange factor Vav3 regulates vascular smooth muscle cell proliferation and migration

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Abstract
Rho guanine nucleotide exchange factors (Rho GEFs) are responsible for Rho protein activation by catalyzing the exchange of GDP for GTP. Although overactivation of Rho proteins is a common component of the pathogenesis of vascular disorders, the molecular mechanisms and the Rho GEFs regulating Rho protein activity and Rho-dependent functions in vascular smooth muscle cells (VSMC) are still unknown. The aim of this study was thus to identify Rho GEFs involved in the regulation of VSMC functions. By a functional screening based on small interfering RNA (siRNA)-mediated silencing of 27 Rho GEFs, we found that only silencing of the Rho GEF Vav3 inhibited rat VSMC proliferation. Conversely, overexpression of Vav3 potentiated VSMC proliferation, whereas the catalytically inactive Vav3 mutant had no effect. The stimulatory effect of Vav3 on VSMC proliferation was inhibited by the Src tyrosine kinase inhibitor SU6656 and by co-expression of the dominant-negative Rac1-N17 mutant. In agreement with this observation, expression of Vav3 induced enrichment of Rac1 to the membrane, activation of its effector PAK, and stimulated VSMC migration. Increased levels of Vav3 transcripts were found in stented arteries and arteries from hypertensive rats. Furthermore, siRNA targeting Vav3 decreased arterial wall cell proliferation. The Rho GEF Vav3 controls VSMC proliferation and migration through activation of Rac1/PAK signalling. Vav3 is a convergent point mediating Rac1 activation in response to different upstream mediators that promote VSMC proliferation and migration and thus appears to be a new potential therapeutic target that could be used to limit vascular proliferative diseases.

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