Reduced vasorelaxation to estradiol and G-1 in aged female and adult male rats is associated with GPR30 downregulation

Abstract

Lindsey SH, da Silva AS, Silva MS, Chappell MC. Reduced vasorelaxation to estradiol and G-1 in aged female and adult male rats is associated with GPR30 downregulation. Am J Physiol Endocrinol Metab 305: E113-E118, 2013. First published May 14, 2013 doi:10.1152/ajpendo.00649.2012.-Previously, we reported that chronic activation of the estrogen receptor GPR30 by its selective agonist G-1 decreases blood pressure in ovariectomized hypertensive mRen2.Lewis (mRen2) rats but not intact male littermates. Furthermore, 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 the potential influence of aging on estrogen receptor expression, we hypothesized that GPR30-dependent vasodilation and receptor expression are altered in males and aged females. Thus, we assessed the response to 17␤-estradiol or G-1 in mesenteric arteries obtained from 15-wk-old normotensive Lewis and hypertensive mRen2 females and males as well as 52-wkold Lewis females. Vasodilation to 17␤-estradiol (E 2) and G-1 was significantly attenuated in 15-wk-old Lewis and mRen2 males compared with age-matched females. Pretreatment of male vessels with the nitric oxide synthase inhibitor L-NAME had no significant effect on the estradiol or G-1 response. In aged females, E 2 and G-1 vasorelaxation was also significantly blunted; however, L-NAME essentially abolished the response. Associated with the reduced vascular responses, GPR30 expression in mesenteric arteries was approximately 50% lower in males and aged females compared with young females. We conclude that alterations in GPR30 expression and signaling may contribute to vascular dysfunction in aging females and a greater blood pressure in hypertensive males.

Estrogen Receptor Subtypes Mediate Distinct Microvascular Dilation and Reduction in [Ca2+]i in Mesenteric Microvessels of Female Rat

“…Consistent with our previous observations (Reslan et al, 2013), lower concentrations of the ER agonists (10 213 to 10 210 M) did not show measureable changes in microvessel diameter or [Ca 21 ] i and therefore were not shown. Also, in agreement with previous ex vivo studies (Lindsey et al, 2013;Reslan et al, 2013), micromolar concentrations of ER agonists (10 26 to 10 25 M) were needed to elicit maximal microvascular relaxation. In accordance with our observations in the main mesenteric artery (Reslan et al, 2013), the inhibitory effects of PPT, DPN, and G1 on Phe contraction were prevented in microvessels pretreated with the ERa antagonist MPP, ERb antagonist PHTPP, and GPR30 antagonist G15, respectively (Table 1), supporting specificity of the relaxation effects of ER agonists.…”

Imbalance between proliferation and apoptosis−related impaired GPR30 expression is involved in preeclampsia

“…In addition to previous observations that GPR30 displays anti-inflammatory [18], proliferative [19] and vasorelaxant functions [13] in HUVECs, we were able to demonstrate migratory and angiogenic properties. Following an H/R insult, in vitro tube formation and migration of HUVECs was compromised, however, pharmacological activation of GPR30 was able to preserve in vitro tube formation and the migratory properties of HUVECs.…”

“…As a novel oestrogen receptor, GPR30 has been shown to regulate many of the rapid vascular effects attributable to oestrogens [16], moreover, multiple studies have demonstrated that GPR30 is associated with the pathogenesis of hypertension [9,[11][12][13][14][15]. Together, these findings suggest a potential role of GPR30 in PE development.…”

“…Accumulated evidence reveals that GPR30 is associated with the pathogenesis of hypertension [9,[11][12][13][14][15]. Since hypertension is one of the defining symptoms of PE we hypothesised that GPR30 might be involved in the pathogenesis of PE.…”

Adaptive increases in expression and vasodilator activity of estrogen receptor subtypes in a blood vessel-specific pattern during pregnancy

“…ER␣ and ER␤ mediate many of the genomic effects of E 2 (68,78,93), and surface membrane ER␣ and ER␤ have been implicated in the rapid vasodilator effects of E 2 (53). A transmembrane G protein-coupled ER (GPER; G protein-coupled receptor 30) may also bind E 2 and mediate some of its nongenomic effects (20,26,43,44,55,58,71,73). Because different tissues may have different blood flow requirements, the vasodilator effects of E 2 /ERs could vary in different vascular beds.…”