title: Genetic dissection of the vav2-rac1 signaling axis in vascular smooth muscle cells.
abstract: Vascular smooth muscle cells (vSMCs) are key in the regulation of blood pressure and the engagement of vascular pathologies, such as hypertension, arterial remodeling, and neointima formation. The role of the Rac1 GTPase in these cells remains poorly characterized. To clarify this issue, we have utilized genetically engineered mice to manipulate the signaling output of Rac1 in these cells at will using inducible, Cre-loxP-mediated DNA recombination techniques. Here, we show that the expression of an active version of the Rac1 activator Vav2 exclusively in vSMCs leads to hypotension as well as the elimination of the hypertension induced by the systemic loss of wild-type Vav2. Conversely, the specific depletion of Rac1 in vSMCs causes defective nitric oxide vasodilation responses and hypertension. Rac1, but not Vav2, also is important for neointima formation but not for hypertension-driven vascular remodeling. These animals also have allowed us to dismiss etiological connections between hypertension and metabolic disease and, most importantly, identify pathophysiological programs that cooperate in the development and consolidation of hypertensive states caused by local vascular tone dysfunctions. Finally, our results suggest that the therapeutic inhibition of Rac1 will be associated with extensive cardiovascular system-related side effects and identify pharmacological avenues to circumvent them.
authors.affiliation: Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC) and University of Salamanca, Campus Unamuno, Salamanca, Spain Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC) and University of Salamanca, Campus Unamuno, Salamanca, Spain.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Fabbiano
authors.affiliation: Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC) and University of Salamanca, Campus Unamuno, Salamanca, Spain Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC) and University of Salamanca, Campus Unamuno, Salamanca, Spain.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Menacho-Márquez
authors.affiliation: Departamento de Fisiología y Farmacología, University of Salamanca, Campus Unamuno, Salamanca, Spain.
authors.forename: María A
authors.initials: MA
authors.lastname: Sevilla
authors.affiliation: Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Julián
authors.initials: J
authors.lastname: Albarrán-Juárez
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Children's Hospital Research Foundation, Cincinnati, Ohio, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.affiliation: Departamento de Fisiología y Farmacología, University of Salamanca, Campus Unamuno, Salamanca, Spain.
authors.forename: María J
authors.initials: MJ
authors.lastname: Montero
authors.affiliation: Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC) and University of Salamanca, Campus Unamuno, Salamanca, Spain Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC) and University of Salamanca, Campus Unamuno, Salamanca, Spain xbustelo@usal.es.
authors.forename: Xosé R
authors.identifier: http://orcid.org/0000-0001-9398-6072
authors.initials: XR
authors.lastname: Bustelo
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D007022:Hypotension / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D058426:Neointima / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics* / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D020830:rac1 GTP-Binding Protein / Q000235:genetics* / Q000378:metabolism*
chemical_list: D009479:Neuropeptides; D051567:Proto-Oncogene Proteins c-vav; C484602:Rac1 protein, mouse; D014665:Vasodilator Agents; C490565:Vav2 protein, mouse; D009569:Nitric Oxide; D020830:rac1 GTP-Binding Protein; D000109:Acetylcholine