| The Rho/Rac exchange factor Vav2 controls nitric oxide-dependent responses in mouse vascular smooth muscle cells. | |
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MedLine Citation:
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PMID: 20038798 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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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Authors:
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Vincent Sauzeau; María A Sevilla; María J Montero; Xosé R Bustelo |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2009-12-14 |
Journal Detail:
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Title: The Journal of clinical investigation Volume: 120 ISSN: 1558-8238 ISO Abbreviation: J. Clin. Invest. Publication Date: 2010 Jan |
Date Detail:
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Created Date: 2010-01-06 Completed Date: 2010-01-20 Revised Date: 2012-02-07 |
Medline Journal Info:
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Nlm Unique ID: 7802877 Medline TA: J Clin Invest Country: United States |
Other Details:
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Languages: eng Pagination: 315-30 Citation Subset: AIM; IM |
Affiliation:
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Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer, CSIC-University of Salamanca, Campus Unamuno, Salamanca, Spain. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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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:
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5R01CA73735/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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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 | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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