Hypertension and prolonged vasoconstrictor signaling in RGS2-deficient mice.
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.
Heximer
Scott P
SP
Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Knutsen
Russell H
RH
Sun
Xiaoguang
X
Kaltenbronn
Kevin M
KM
Rhee
Man-Hee
MH
Peng
Ning
N
Oliveira-dos-Santos
Antonio
A
Penninger
Josef M
JM
Muslin
Anthony J
AJ
Steinberg
Thomas H
TH
Wyss
J Michael
JM
Mecham
Robert P
RP
Blumer
Kendall J
KJ
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
D020710:RGS Proteins; C105345:Rgs2 protein, mouse; D014662:Vasoconstrictor Agents; D000804:Angiotensin II