| First Author | Sauzeau V | Year | 2010 |
| Journal | J Clin Invest | Volume | 120 |
| Issue | 1 | Pages | 315-30 |
| PubMed ID | 20038798 | Mgi Jnum | J:156698 |
| Mgi Id | MGI:4421242 | Doi | 10.1172/JCI38356 |
| Citation | Sauzeau V, et al. (2010) The Rho/Rac exchange factor Vav2 controls nitric oxide-dependent responses in mouse vascular smooth muscle cells. J Clin Invest 120(1):315-30 |
| abstractText | 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. |
