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 5

Options: View larger image (or click on image) Download as PowerPoint
Changes in intracellular calcium levels in response to vasoconstrictors ...
Changes in intracellular calcium levels in response to vasoconstrictors in primary aortic vascular smooth muscle cells derived from wild-type and rgs2–/– mice. (a) Dose-response relationships for P2Y receptor–mediated increases in intracellular calcium levels. Cells were treated with the indicated doses of ATP, an agonist for P2Y receptors. Changes in intracellular calcium levels were measured as changes in fluorescence ratio [FR ± SEM = (emission at 510 nm upon excitation at 340 nm)/(emission at 510 nm upon excitation at 380 nm)] in fura-2–loaded cells isolated from wild-type (n = 15–22 individual cells for each agonist dose; open squares) and rgs2–/– mice (n = 15–22 individual cells for each agonist dose; filled squares). (b) Rates of intracellular calcium level decay (100% × [FR – FRfinal]/[FRinitial – FRfinal] ± SEM) after a maximal response had been elicited by treating cells from wild-type (n = 39 individual cells; open squares) and rgs2–/– mice (n = 46 individual cells; filled squares) with 100 μM ATP. Pairwise comparisons of the FR values of wild-type and rgs2–/– cells were made at similar agonist concentrations in a or similar times after maximal FR response in b. Statistically significant differences are indicated (*P < 0.001).