title: The Rho/Rac exchange factor Vav2 controls nitric oxide-dependent responses in mouse vascular smooth muscle cells.
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.affiliation: Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer, CSIC-University of Salamanca, Campus Unamuno, Salamanca, Spain.
authors.forename: Vincent
authors.initials: V
authors.lastname: Sauzeau
authors.forename: María A
authors.initials: MA
authors.lastname: Sevilla
authors.forename: María J
authors.initials: MJ
authors.lastname: Montero
authors.forename: Xosé R
authors.initials: XR
authors.lastname: Bustelo
mesh_terms: D000818:Animals; D006152:Cyclic GMP / Q000096:biosynthesis; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000502:physiology; D006973:Hypertension / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000502:physiology*; D009479:Neuropeptides / Q000502:physiology; D009569:Nitric Oxide / Q000502:physiology*; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines / Q000494:pharmacology; D051567:Proto-Oncogene Proteins c-vav / Q000502:physiology*; D011687:Purines / Q000494:pharmacology; D015398:Signal Transduction; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology; D014664:Vasodilation; D054462:p21-Activated Kinases / Q000502:physiology; D020744:rac GTP-Binding Proteins / Q000502:physiology; D020830:rac1 GTP-Binding Protein; D054460:rho-Associated Kinases / Q000502:physiology; D020742:rhoA GTP-Binding Protein / Q000502:physiology
chemical_list: D009479:Neuropeptides; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D051567:Proto-Oncogene Proteins c-vav; D011687:Purines; C484602:Rac1 protein, mouse; D013450:Sulfones; C490565:Vav2 protein, mouse; C496622:Vav3 protein, mouse; D009569:Nitric Oxide; D000068677:Sildenafil Citrate; C515905:Pak1 protein, mouse; D054462:p21-Activated Kinases; D054460:rho-Associated Kinases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein; D006152:Cyclic GMP