title: Smooth muscle specific Rac1 deficiency induces hypertension by preventing p116RIP3-dependent RhoA inhibition.
abstract: BACKGROUND
  Increasing evidence implicates overactivation of RhoA as a critical component of the pathogenesis of hypertension. Although a substantial body of work has established that Rac1 functions antagonize RhoA in a broad range of physiological processes, the role of Rac1 in the regulation of vascular tone and blood pressure is not fully elucidated.
  
  
  RESULTS
  To define the role of Rac1 in vivo in vascular smooth muscle cells (vSMC), we generated smooth muscle (SM)-specific Rac1 knockout mice (SM-Rac1-KO) and performed radiotelemetric blood pressure recordings, contraction measurements in arterial rings, vSMC cultures and biochemical analyses. SM-Rac1-KO mice develop high systolic blood pressure sensitive to Rho kinase inhibition by fasudil. Arteries from SM-Rac1-KO mice are characterized by a defective NO-dependent vasodilation and an overactivation of RhoA/Rho kinase signaling. We provide evidence that Rac1 deletion-induced hypertension is due to an alteration of cGMP signaling resulting from the loss of Rac1-mediated control of type 5 PDE activity. Consequently, cGMP-dependent phosphorylation and binding of RhoA with its inhibitory partner, the phosphatase-RhoA interacting protein (p116(RIP3)), are decreased.
  
  
  CONCLUSIONS
  Our data reveal that the depletion of Rac1 in SMC decreases cGMP-dependent p116(RIP3)/RhoA interaction and the subsequent inhibition of RhoA signaling. Thus, we unveil an in vivo role of Rac1 in arterial blood pressure regulation and a new pathway involving p116(RIP3) that contributes to the antagonistic relationship between Rac1 and RhoA in vascular smooth muscle cells and their opposite roles in arterial tone and blood pressure.
authors.affiliation: Inserm UMR_S1087, CNRS UMR_C6291, l'institut du thorax, Nantes, F-44000, France (G.A., J.E.S., G.T., M.R.D., G.L., V.S.) Université de Nantes, Nantes, F-44000, France (G.A., J.E.S., G.T., M.R.D., G.L., V.S.).
authors.forename: Gwennan
authors.initials: G
authors.lastname: André
authors.affiliation: Inserm UMR_S1087, CNRS UMR_C6291, l'institut du thorax, Nantes, F-44000, France (G.A., J.E.S., G.T., M.R.D., G.L., V.S.) Université de Nantes, Nantes, F-44000, France (G.A., J.E.S., G.T., M.R.D., G.L., V.S.).
authors.forename: Juan E
authors.initials: JE
authors.lastname: Sandoval
authors.affiliation: Inserm UMR_S1083, CNRS UMR_C6214, BNMI, Angers, F-49000, France (K.R., L.L.).
authors.forename: Kevin
authors.initials: K
authors.lastname: Retailleau
authors.affiliation: Inserm UMR_S1083, CNRS UMR_C6214, BNMI, Angers, F-49000, France (K.R., L.L.).
authors.forename: Laurent
authors.initials: L
authors.lastname: Loufrani
authors.affiliation: Inserm UMR_S1087, CNRS UMR_C6291, l'institut du thorax, Nantes, F-44000, France (G.A., J.E.S., G.T., M.R.D., G.L., V.S.) Université de Nantes, Nantes, F-44000, France (G.A., J.E.S., G.T., M.R.D., G.L., V.S.).
authors.forename: Gilles
authors.initials: G
authors.lastname: Toumaniantz
authors.affiliation: Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (S.O.).
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.affiliation: Inserm UMR_S1087, CNRS UMR_C6291, l'institut du thorax, Nantes, F-44000, France (G.A., J.E.S., G.T., M.R.D., G.L., V.S.) Université de Nantes, Nantes, F-44000, France (G.A., J.E.S., G.T., M.R.D., G.L., V.S.).
authors.forename: Malvyne
authors.initials: M
authors.lastname: Rolli-Derkinderen
authors.affiliation: Inserm UMR_S1087, CNRS UMR_C6291, l'institut du thorax, Nantes, F-44000, France (G.A., J.E.S., G.T., M.R.D., G.L., V.S.) Université de Nantes, Nantes, F-44000, France (G.A., J.E.S., G.T., M.R.D., G.L., V.S.) CHU Nantes, l'institut du thorax, Nantes, F-44000, France (G.L., V.S.).
authors.forename: Gervaise
authors.initials: G
authors.lastname: Loirand
authors.affiliation: Inserm UMR_S1087, CNRS UMR_C6291, l'institut du thorax, Nantes, F-44000, France (G.A., J.E.S., G.T., M.R.D., G.L., V.S.) Université de Nantes, Nantes, F-44000, France (G.A., J.E.S., G.T., M.R.D., G.L., V.S.) CHU Nantes, l'institut du thorax, Nantes, F-44000, France (G.L., V.S.).
authors.forename: Vincent
authors.initials: V
authors.lastname: Sauzeau
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D004452:Echocardiography; D006973:Hypertension / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000503:physiopathology*; D009479:Neuropeptides / Q000172:deficiency* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D014664:Vasodilation / Q000502:physiology; D020830:rac1 GTP-Binding Protein / Q000172:deficiency* / Q000502:physiology; D020741:rho GTP-Binding Proteins / Q000502:physiology*; D020742:rhoA GTP-Binding Protein
chemical_list: D008840:Microfilament Proteins; D009479:Neuropeptides; C484602:Rac1 protein, mouse; C500243:p116Rip protein, mouse; C526380:RhoA protein, mouse; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein
keywords: blood pressure; hypertension; nitric oxide; signal transduction; vasoconstriction