Abstract 642: GPR30-Mediated Relaxation of Mesenteric Resistance Arteries is Diminished in Males and Aging Females
We previously reported that chronic activation of estrogen receptor GPR30 by the selective agonist G-1 decreases blood pressure in ovariectomized hypertensive mRen2.Lewis rats but not male littermates. Furthermore, acute G-1 relaxes female mesenteric resistance arteries via both endothelium-dependent and -independent mechanisms. Because of the lack of a blood pressure-lowering effect by G-1 in males and because aging may influence estrogen receptor expression, we hypothesized that GPR30-dependent vasodilation was reduced in males and older females. Mesenteric vessels (∼200 μm I.D.) from 15 wk Lewis and mRen2.Lewis males and 52 wk Lewis females were mounted on a wire myograph and preconstricted with 10 μM phenylephrine before assessing the response to increasing concentrations of 17β-estradiol or G-1 (0.001-3 μM). At the highest concentration, 17β-estradiol vasodilation was greater in 15 wk Lewis females (62±8%, n=5) and mRen2.Lewis females (57±9%, n=6) than age-matched Lewis males (33±7%, n=5, P<0.001) and mRen2.Lewis males (30±7%, n=4, P<0.001). The G-1 response was also greater in Lewis females (60±12%, n=7) and mRen2.Lewis females (57±8%, n=5) than in Lewis males (33±8%, n=7, P<0.01) and mRen2.Lewis males (28±7%, n=4, P<0.01). Pretreatment of male vessels with the nitric oxide (NO) synthase inhibitor L-NAME had no significant effect on the estradiol or G-1 response (n=3-6, P>0.05). In aged females, vasorelaxation was also significantly blunted in response to 17β-estradiol (34±6%, n=5, P<0.01) and G-1 (32±6%, n=8, P<0.01). In contrast to males, L-NAME inhibition or endothelial denuding in older females further reduced vasodilation to both 17β-estradiol (L-NAME: 15±6%, n=4, P<0.05; denuded: 13±2%, n=8, P<0.001) and G-1 (L-NAME: 10±6%, n=3, P<0.01; denuded 8±2%, n=11, P<0.0001). In summary, GPR30-mediated vasodilation was attenuated in Lewis and mRen2.Lewis males, and the ineffectiveness of L-NAME inhibition suggests a loss in NO signaling. G-1 vasorelaxation was also blunted in aging Lewis females, but the intact NO response indicates a smooth muscle cell deficit. We conclude that alterations in GPR30 expression or signaling may contribute to the loss of cardiovascular protection in aging postmenopausal females and in adult males.
- © 2012 by American Heart Association, Inc.