Hypertension and prolonged vasoconstrictor signaling in RGS2-deficient mice
Scott P. Heximer, … , Robert P. Mecham, Kendall J. Blumer
Scott P. Heximer, … , Robert P. Mecham, Kendall J. Blumer
Published February 15, 2003
Citation Information: J Clin Invest. 2003;111(4):445-452. https://doi.org/10.1172/JCI15598.
View: Text | PDF | Addendum
Article Cardiology

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

Scott P. Heximer, Russell H. Knutsen, Xiaoguang Sun, Kevin M. Kaltenbronn, Man-Hee Rhee, Ning Peng, Antonio Oliveira-dos-Santos, Josef M. Penninger, Anthony J. Muslin, Thomas H. Steinberg, J. Michael Wyss, Robert P. Mecham, Kendall J. Blumer

×

Figure 3

Options: View larger image (or click on image) Download as PowerPoint
Blood pressure responses following challenge with angiotensin II or AT1 ...
Blood pressure responses following challenge with angiotensin II or AT1 receptor blockade in wild-type and RGS2-deficient mice. (a) Time courses of blood pressure increase (change in MAP ± SEM, mmHg) following intraarterial administration of pressor doses of angiotensin II to RGS2-deficient mice (n = 6; filled squares) and wild-type mice (n = 6; open squares). (b) Time courses of blood pressure decrease (change in MAP ± SEM, mmHg) following AT1 receptor blockade with candesartan in wild-type (n = 6; open squares) and rgs2–/– mice (n = 6; filled squares). (c) Time course of blood pressure decrease [(MAP – MAPfinal)/(MAPinitial – MAPfinal)] ± SEM following AT1 receptor blockade in wild-type (n = 7; open squares) and rgs2–/– mice (n = 7; filled squares) that were pretreated with a pressor dose of angiotensin II to elevate blood pressures to similarly high starting values (systolic blood pressure = 160–170 mmHg). The results shown in each panel are representative of more than ten experiments performed with each genotype. The changes in blood pressure for wild-type and rgs2–/– mice were compared at each time point. Statistically significant differences are indicated (*P < 0.01, **P < 0.002). (d) Western blot analysis of AT1 receptors in aortic extracts. AT1 receptor expression in aortae from wild-type rats and rgs2+/+ (WT), rgs2+/–, and rgs2–/– mice is indicated (upper panel). Antibody specificity was verified by probing of an identical blot with primary antibody that first had been incubated with blocking peptide (lower panel).