title: Regulator of G-protein signaling 5 controls blood pressure homeostasis and vessel wall remodeling.
abstract: BACKGROUND
  Regulator of G-protein signaling 5 (RGS5) modulates G-protein-coupled receptor signaling and is prominently expressed in arterial smooth muscle cells. Our group first reported that RGS5 is important in vascular remodeling during tumor angiogenesis. We hypothesized that RGS5 may play an important role in vessel wall remodeling and blood pressure regulation.
  
  
  OBJECTIVE
  To demonstrate that RGS5 has a unique and nonredundant role in the pathogenesis of hypertension and to identify crucial RGS5-regulated signaling pathways.
  
  
  RESULTS
  We observed that arterial RGS5 expression is downregulated with chronically elevated blood pressure after angiotensin II infusion. Using a knockout mouse model, radiotelemetry, and pharmacological inhibition, we subsequently showed that loss of RGS5 results in profound hypertension. RGS5 signaling is linked to the renin-angiotensin system and directly controls vascular resistance, vessel contractility, and remodeling. RGS5 deficiency aggravates pathophysiological features of hypertension, such as medial hypertrophy and fibrosis. Moreover, we demonstrate that protein kinase C, mitogen-activated protein kinase/extracellular signal-regulated kinase, and Rho kinase signaling pathways are major effectors of RGS5-mediated hypertension.
  
  
  CONCLUSIONS
  Loss of RGS5 results in hypertension. Loss of RGS5 signaling also correlates with hyper-responsiveness to vasoconstrictors and vascular stiffening. This establishes a significant, distinct, and causal role of RGS5 in vascular homeostasis. RGS5 modulates signaling through the angiotensin II receptor 1 and major Gαq-coupled downstream pathways, including Rho kinase. So far, activation of RhoA/Rho kinase has not been associated with RGS molecules. Thus, RGS5 is a crucial regulator of blood pressure homeostasis with significant clinical implications for vascular pathologies, such as hypertension.
authors.affiliation: Western Australian Institute for Medical Research, Rear, 50 Murray St, Perth, WA 6010, Australia.
authors.forename: Vasyl
authors.initials: V
authors.lastname: Holobotovskyy
authors.forename: Mitali
authors.initials: M
authors.lastname: Manzur
authors.forename: Marianne
authors.initials: M
authors.lastname: Tare
authors.forename: Jennifer
authors.initials: J
authors.lastname: Burchell
authors.forename: Erin
authors.initials: E
authors.lastname: Bolitho
authors.forename: Helena
authors.initials: H
authors.lastname: Viola
authors.forename: Livia C
authors.initials: LC
authors.lastname: Hool
authors.forename: Leonard F
authors.initials: LF
authors.lastname: Arnolda
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: McKitrick
authors.forename: Ruth
authors.initials: R
authors.lastname: Ganss
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D001808:Blood Vessels / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D006706:Homeostasis / Q000502:physiology*; D006973:Hypertension / Q000503:physiopathology; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D011493:Protein Kinase C / Q000502:physiology; D020710:RGS Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D014661:Vasoconstriction / Q000502:physiology; D054460:rho-Associated Kinases / Q000502:physiology
chemical_list: D020710:RGS Proteins; C105346:Rgs5 protein, mouse; D054460:rho-Associated Kinases; D011493:Protein Kinase C