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Usage Information

The Rho/Rac exchange factor Vav2 controls nitric oxide–dependent responses in mouse vascular smooth muscle cells
Vincent Sauzeau, … , María J. Montero, Xosé R. Bustelo
Vincent Sauzeau, … , María J. Montero, Xosé R. Bustelo
Published December 14, 2009
Citation Information: J Clin Invest. 2010;120(1):315-330. https://doi.org/10.1172/JCI38356.
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Research Article Vascular biology

The Rho/Rac exchange factor Vav2 controls nitric oxide–dependent responses in mouse vascular smooth muscle cells

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Abstract

The regulation of arterial contractility is essential for blood pressure control. The GTPase RhoA promotes vasoconstriction by modulating the cytoskeleton of vascular smooth muscle cells. Whether other Rho/Rac pathways contribute to blood pressure regulation remains unknown. By studying a hypertensive knockout mouse lacking the Rho/Rac activator Vav2, we have discovered a new signaling pathway involving Vav2, the GTPase Rac1, and the serine/threonine kinase Pak that contributes to nitric oxide–triggered blood vessel relaxation and normotensia. This pathway mediated the Pak-dependent inhibition of phosphodiesterase type 5, a process that favored RhoA inactivation and the subsequent depolymerization of the F-actin cytoskeleton in vascular smooth muscle cells. The inhibition of phosphodiesterase type 5 required its physical interaction with autophosphorylated Pak1 but, unexpectedly, occurred without detectable transphosphorylation events between those 2 proteins. The administration of phosphodiesterase type 5 inhibitors prevented the development of hypertension and cardiovascular disease in Vav2-deficient animals, demonstrating the involvement of this new pathway in blood pressure regulation. Taken together, these results unveil one cause of the cardiovascular phenotype of Vav2-knockout mice, identify a new Rac1/Pak1 signaling pathway, and provide a mechanistic framework for better understanding blood pressure control in physiological and pathological states.

Authors

Vincent Sauzeau, María A. Sevilla, María J. Montero, Xosé R. Bustelo

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