Document Detail


The Rho/Rac exchange factor Vav2 controls nitric oxide-dependent responses in mouse vascular smooth muscle cells.
MedLine Citation:
PMID:  20038798     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Vincent Sauzeau; María A Sevilla; María J Montero; Xosé R Bustelo
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2009-12-14
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  120     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2010 Jan 
Date Detail:
Created Date:  2010-01-06     Completed Date:  2010-01-20     Revised Date:  2012-02-07    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  315-30     Citation Subset:  AIM; IM    
Affiliation:
Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer, CSIC-University of Salamanca, Campus Unamuno, Salamanca, Spain.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cyclic GMP / biosynthesis
Cyclic Nucleotide Phosphodiesterases, Type 5 / physiology
Hypertension / prevention & control
Mice
Mice, Inbred C57BL
Muscle, Smooth, Vascular / physiology*
Myocytes, Smooth Muscle / physiology*
Neuropeptides / physiology
Nitric Oxide / physiology*
Phosphodiesterase 5 Inhibitors
Piperazines / pharmacology
Proto-Oncogene Proteins c-vav / physiology*
Purines / pharmacology
Signal Transduction
Sulfones / pharmacology
Vasodilation
p21-Activated Kinases / physiology
rac GTP-Binding Proteins / physiology
rho-Associated Kinases / physiology
rhoA GTP-Binding Protein / physiology
Grant Support
ID/Acronym/Agency:
5R01CA73735/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Neuropeptides; 0/Pak1 protein, mouse; 0/Phosphodiesterase 5 Inhibitors; 0/Piperazines; 0/Proto-Oncogene Proteins c-vav; 0/Purines; 0/Rac1 protein, mouse; 0/Sulfones; 0/Vav2 protein, mouse; 0/Vav3 protein, mouse; 10102-43-9/Nitric Oxide; 139755-83-2/sildenafil; 7665-99-8/Cyclic GMP; EC 2.7.11.1/p21-Activated Kinases; EC 2.7.11.1/rho-Associated Kinases; EC 3.1.4.35/Cyclic Nucleotide Phosphodiesterases, Type 5; EC 3.6.5.2/rac GTP-Binding Proteins; EC 3.6.5.2/rhoA GTP-Binding Protein
Comments/Corrections

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