title: Hypertension and prolonged vasoconstrictor signaling in RGS2-deficient mice.
abstract: Signaling by hormones and neurotransmitters that activate G protein-coupled receptors (GPCRs) maintains blood pressure within the normal range despite large changes in cardiac output that can occur within seconds. This implies that blood pressure regulation requires precise kinetic control of GPCR signaling. To test this hypothesis, we analyzed mice deficient in RGS2, a GTPase-activating protein that greatly accelerates the deactivation rate of heterotrimeric G proteins in vitro. Both rgs2+/- and rgs2-/- mice exhibited a strong hypertensive phenotype, renovascular abnormalities, persistent constriction of the resistance vasculature, and prolonged response of the vasculature to vasoconstrictors in vivo. Analysis of P2Y receptor-mediated Ca2+ signaling in vascular smooth muscle cells in vitro indicated that loss of RGS2 increased agonist potency and efficacy and slowed the kinetics of signal termination. These results establish that abnormally prolonged signaling by G protein-coupled vasoconstrictor receptors can contribute to the onset of hypertension, and they suggest that genetic defects affecting the function or expression of RGS2 may be novel risk factors for development of hypertension in humans.
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Scott P
authors.initials: SP
authors.lastname: Heximer
authors.forename: Russell H
authors.initials: RH
authors.lastname: Knutsen
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Sun
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Kaltenbronn
authors.forename: Man-Hee
authors.initials: MH
authors.lastname: Rhee
authors.forename: Ning
authors.initials: N
authors.lastname: Peng
authors.forename: Antonio
authors.initials: A
authors.lastname: Oliveira-dos-Santos
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Muslin
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Steinberg
authors.forename: J Michael
authors.initials: JM
authors.lastname: Wyss
authors.forename: Robert P
authors.initials: RP
authors.lastname: Mecham
authors.forename: Kendall J
authors.initials: KJ
authors.lastname: Blumer
mesh_terms: D000804:Angiotensin II / Q000502:physiology; D000818:Animals; D020013:Calcium Signaling; D002478:Cells, Cultured; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D006973:Hypertension / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000503:physiopathology; D010641:Phenotype; D020710:RGS Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D020710:RGS Proteins; C105345:Rgs2 protein, mouse; D014662:Vasoconstrictor Agents; D000804:Angiotensin II