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

Content Provider	PubMed Central
Author	Vincent, Sauzeau Sevilla, María A. Montero, María J. Bustelo, Xosé R.
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.
Related Links	http://dx.doi.org/10.1172/jci38356
Ending Page	330
Page Count	16
Starting Page	315
File Format	PDF
ISSN	00219738
e-ISSN	15588238
Journal	The Journal of Clinical Investigation
Issue Number	1
Volume Number	120
Language	English
Publisher	American Society for Clinical Investigation
Publisher Date	2010-01-04
Access Restriction	Open
Rights Holder	American Society for Clinical Investigation
Subject Keyword	Medicine(all) Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Medicine

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4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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