title: Age-dependent blood pressure elevation is due to increased vascular smooth muscle tone mediated by G-protein signalling.
abstract: OBJECTIVE
  Arterial hypertension is a major risk factor for cardiovascular diseases. The kidney and its natriuretic function are in the centre of the prevailing models to explain the pathogenesis of hypertension; however, the mechanisms underlying blood pressure elevation remain unclear in most patients. Development of hypertension is strongly correlated with age, and this blood pressure increase typically accelerates in the fourth decade of life. The cause of age-dependent blood pressure elevation is poorly understood. This study aims to understand the role of procontractile G-protein-mediated signalling pathways in vascular smooth muscle in age-dependent hypertension.
  
  
  RESULTS
  Similar to humans at mid-life, we observed in 1-year-old mice elevated blood pressure levels without any evidence for increased vessel stiffness, impaired renal function, or endocrine abnormalities. Hypertensive aged mice showed signs of endothelial dysfunction and had an increased vascular formation of reactive oxygen species (ROS) and elevated endothelial ET-1 expression. Age-dependent hypertension could be normalized by ETA receptor blockade, smooth muscle-specific inactivation of the gene encoding the ETA receptor, as well as by acute disruption of downstream signalling via induction of smooth muscle-specific Gα12/Gα13, Gαq/Gα11, or LARG deficiency using tamoxifen-inducible smooth muscle-specific conditional mouse knock-out models. Induction of smooth muscle-specific ETA receptor deficiency normalized the blood pressure in aged mice despite the continuous presence of signs of endothelial dysfunction.
  
  
  CONCLUSIONS
  Age-dependent blood pressure elevation is due to a highly reversible activation of procontractile signalling in vascular smooth muscle cells indicating that increased vascular tone can be a primary factor in the development of hypertension.
authors.affiliation: Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Ludwigstr. 43, 61231 Bad Nauheim, Germany Institute of Pharmacology, University of Heidelberg, ImNeuenheimer Feld 366, 69120 Heidelberg, Germany angela.wirth@pharma.uni-heidelberg stefan.offermanns@mpi-bn.mpg.de.
authors.forename: Angela
authors.initials: A
authors.lastname: Wirth
authors.affiliation: Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Ludwigstr. 43, 61231 Bad Nauheim, Germany.
authors.forename: Shengpeng
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Ludwigstr. 43, 61231 Bad Nauheim, Germany.
authors.forename: Mikito
authors.initials: M
authors.lastname: Takefuji
authors.affiliation: Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Ludwigstr. 43, 61231 Bad Nauheim, Germany.
authors.forename: Cong
authors.initials: C
authors.lastname: Tang
authors.affiliation: Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Ludwigstr. 43, 61231 Bad Nauheim, Germany.
authors.forename: Till F
authors.initials: TF
authors.lastname: Althoff
authors.affiliation: Institute of Physiology, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Schweda
authors.affiliation: Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Ludwigstr. 43, 61231 Bad Nauheim, Germany Medical Faculty, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Wettschureck
authors.affiliation: Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Ludwigstr. 43, 61231 Bad Nauheim, Germany Medical Faculty, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany angela.wirth@pharma.uni-heidelberg stefan.offermanns@mpi-bn.mpg.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
mesh_terms: D000367:Age Factors; D000818:Animals; D019332:Endothelin-1 / Q000502:physiology; D019204:GTP-Binding Proteins / Q000502:physiology*; D006973:Hypertension / Q000209:etiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000502:physiology; D044022:Receptor, Endothelin A / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D019332:Endothelin-1; D044022:Receptor, Endothelin A; D019204:GTP-Binding Proteins
keywords: Ageing; Blood pressure; Endothelin; Hypertension; Smooth muscle