Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 120, Issue 1, Pages 315-330Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI38356
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Funding
- NIH [5R01CA73735]
- Spanish Ministry of Science and Innovation (MST) [SAF2006-01789]
- Red Tematica de I nvestigacion Cooperariva en Cancer [RD06/0020/0001]
- Castilla y Leon Autonomous Government [SA053A05, GR97]
- European Molecular Biology Organization (EMBO)
- MST Juan de la Cierva
- MSI/CSIC Ramon y Cajal
- NATIONAL CANCER INSTITUTE [R01CA073735] Funding Source: NIH RePORTER
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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.
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