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Título

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

AutorSauzeau, Vincent; Sevilla, Mª Ángeles; Montero, María J.; Bustelo, Xosé R.
Fecha de publicación4-ene-2010
EditorAmerican Society for Clinical Investigation
CitaciónJournal of Clinical Investigation 20(1): 315–330 (2010)
ResumenThe 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.
Versión del editorhttp://dx.doi.org/10.1172/JCI38356
URIhttp://hdl.handle.net/10261/45930
DOI10.1172/JCI38356
ISSN0021-9738
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