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Título: | The Rho/Rac exchange factor Vav2 controls nitric oxide–dependent responses in mouse vascular smooth muscle cells |
Autor: | Sauzeau, Vincent; Sevilla, Mª Ángeles; Montero, María J.; Bustelo, Xosé R. CSIC ORCID | Fecha de publicación: | 4-ene-2010 | Editor: | American Society for Clinical Investigation | Citación: | Journal of Clinical Investigation 20(1): 315–330 (2010) | Resumen: | 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. | Versión del editor: | http://dx.doi.org/10.1172/JCI38356 | URI: | http://hdl.handle.net/10261/45930 | DOI: | 10.1172/JCI38356 | ISSN: | 0021-9738 |
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