Activation of G protein-coupled estrogen receptor induces endothelium-independent relaxation of coronary artery smooth muscle (original) (raw)
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Pharmacology, 2010
Coronary artery disease, which predominantly affects epicardial coronary arteries , represents the leading cause of death worldwide in women and men alike . Endogenous estrogens protect from development of coronary atherosclerosis in premenopausal women and are involved in the regulation of vascular tone and, thus, blood pressure [4] . These effects have mainly been attributed to activation of estrogen receptors (ER) ␣ and  [3] . Natural estrogen (17  -estradiol) acutely dilates human and porcine coronary arteries , and also inhibits responses to vasoconstrictors [6-9] . Using selective agonists for either ER ␣ or ER  , individual roles of these receptors mediating dilation of coronary arteries have been demonstrated .
Journal of Vascular Research, 2013
The G protein-coupled estrogen receptor GPER1/GPR30 is implicated in blood pressure regulation but the mechanisms are not identified. Here, we hypothesize that GPER1 controls blood pressure by regulating vascular smooth muscle cell Ca2+ handling. Treatment with the GPER1 agonist G-1 (in the µM concentration range) acutely reduced spontaneous and synchronous Ca2+ spike activity in A7r5 vascular smooth muscle cells expressing mRNA for GPER1. Furthermore, G-1 (1 µM) attenuated the thromboxane A2 analogue U46619-stimulated Ca2+ spike activity but had no effect on the U46619-induced increase in the basal level of Ca2+. The voltage-sensitive L-type Ca2+ channel blocker nifedipine (100 nM) reduced Ca2+ spike activity similar to G-1. Pharmacological, but not physiological, concentrations of the estrogen 17β-estradiol reduced Ca2+ spike activity. The GPER1 antagonist G-15 blocked G-1-induced downregulation of Ca2+ spike activity, supporting a GPER1-dependent mechanism. G-1 (1 µM) and nifedip...
PloS one, 2013
Vascular pathology and dysfunction are direct life-threatening outcomes resulting from atherosclerosis or vascular injury, which are primarily attributed to contractile smooth muscle cells (SMCs) dedifferentiation and proliferation by re-entering cell cycle. Increasing evidence suggests potent protective effects of G-protein coupled estrogen receptor 1 (GPER) activation against cardiovascular diseases. However, the mechanism underlying GPER function remains poorly understood, especially if it plays a potential role in modulating coronary artery smooth muscle cells (CASMCs). The objective of our study was to understand the functional role of GPER in CASMC proliferation and differentiation in coronary arteries using from humans and swine models. We found that the GPER agonist, G-1, inhibited both human and porcine CASMC proliferation in a concentration- (10(-8) to 10(-5) M) and time-dependent manner. Flow cytometry revealed that treatment with G-1 significantly decreased the proportio...
The G protein-coupled estrogen receptor GPER/GPR30 as a regulator of cardiovascular function
Vascular Pharmacology, 2011
Endogenous estrogens are important regulators of cardiovascular homeostasis in premenopausal women and interfere with the development of hypertension and coronary artery disease. These hormones act via three different estrogen receptors affecting both gene transcription and rapid signaling pathways in a complex interplay. In addition to the classical estrogen receptors ERα and ERβ, which are known mediators of estrogen-dependent vascular effects, a G protein-coupled estrogen receptor termed GPER that is expressed in the cardiovascular system has recently been identified. Endogenous human 17β-estradiol, selective estrogen receptor modulators (SERMs) including tamoxifen and raloxifene, and selective estrogen receptor downregulators (SERDs) such as ICI 182,780 are all agonists of GPER, which has been implicated in the regulation of vasomotor tone and protection from myocardial ischemia/reperfusion injury. As a result, understanding the individual role of ERα, ERβ, and GPER in cardiovascular function has become increasingly complex. With accumulating evidence that GPER is responsible for a variety of beneficial cardiovascular effects of estrogens, this receptor may represent a novel target to develop effective strategies for the treatment of cardiovascular diseases by tissue-specific, selective activation of estrogen-dependent molecular pathways devoid of side effects seen with conventional hormone therapy.
Maturitas, 2014
G-protein-coupled estrogen receptors (GPERs) have been proposed to mediate estrogen-mediated vasodilation. The presence of GPER-dependent vasodilation in human resistance-sized arteries (HRAs) or its signal transduction pathways have not been investigated. HRAs in subcutaneous fat tissues (biopsies from postmenopausal women (PMW), age-matched men (M) and pregnant women (PGW)) were mounted for in vitro isometric force recording. Vasodilation induced by G-1 (selective GPER-agonist, 3 M) from HRAs pre-contracted with norepinephrine amounted to 40 ± 5% in PMW, significantly larger than those obtained from M (20 ± 5%) or PGW (20 ± 5%). l-NAME (nitric oxide (NO) synthase inhibitor) abolished these relaxations in PGW, attenuated them in PMW and had no effect in M. Immunohistochemical analysis confirmed the presence of GPER in both smooth muscle and endothelial cells of HRA with maximum expression in PGW. In cultured human umbilical vein endothelial cells (HUVECs), G-1 increased NO-synthesis concentration-dependently through higher expressions of endothelial NO-synthase (eNOS) and through enhanced phosphorylation of eNOS on Ser 1177. In conclusion, GPER vasodilates human resistance arteries through various activating mechanisms of the eNOS-signaling pathway.
Hypertension (Dallas, Tex. : 1979), 2016
Estrogens are important regulators of cardiovascular function. Some of estrogen's cardiovascular effects are mediated by a G-protein-coupled receptor mechanism, namely, G-protein-coupled estrogen receptor (GPER). Estradiol-mediated regulation of vascular cell programmed cell death reflects the balance of the opposing actions of GPER versus estrogen receptor α (ERα). However, the significance of these opposing actions on the regulation of vascular smooth muscle cell proliferation or migration in vitro is unclear, and the significance in vivo is unknown. To determine the effects of GPER activation in vitro, we studied rat aortic vascular smooth muscle cells maintained in primary culture. GPER was reintroduced using adenoviral gene transfer. Both estradiol and G1, a GPER agonist, inhibited both proliferation and cell migration effects that were blocked by the GPER antagonist, G15. To determine the importance of the GPER-ERα balance in regulating vascular remodeling in a rat model o...
Cardiovascular Research, 2002
Objective: Postmenopausal estrogen replacement therapy lowers the incidence of cardiovascular disease, suggesting that estrogens support cardiovascular function. Estrogens dilate coronary arteries; however, little is known about the molecular basis of how estrogen affects the human coronary circulation. The cellular / molecular effects of estrogen action on human coronary smooth muscle were investigated in the present study. Methods: Patch-clamp and fluorescent microscopy studies were performed on human coronary myocytes in the absence of endothelium. Results: Estrogen increased whole-cell currents over a range of membrane potentials, and further studies indicated that the large-conductance (186.563 pS), calcium-and voltage-activated potassium (BK) channel was the Ca target of estrogen action. Channel activity was stimulated |15-fold by nanomolar concentrations of 17b-estradiol, and this stimulation was reversed .90% by inhibiting cGMP-dependent protein kinase activity with 300 nM KT5823. 17b-Estradiol increased the level of cGMP and nitric oxide in human myocytes, and the stimulatory effect of estrogen on channel activity and NO production was reversed by G inhibiting NO synthase with 10 mM N-monomethyl-L-arginine. Conclusions: Our cellular and molecular studies identify the BK Ca channel as a target of estrogen action in human coronary artery smooth muscle. This response to estrogen involves cGMP-dependent phosphorylation of the BK channel or a closely associated regulatory molecule, and further evidence suggests involvement of the Ca NO / cGMP signaling system in coronary smooth muscle. These findings are the first to provide direct evidence for a molecular mechanism that can account for endothelium-independent effects of estrogen on human arteries, and may also help explain why estrogens reduce myocardial ischemia and stimulate coronary blood flow in patients with diseased coronary arteries.
GPER modulates tone and coronary vascular reactivity in male and female rats
Journal of Molecular Endocrinology, 2017
Compared with age-matched men, premenopausal women are largely protected from coronary artery disease, a difference that is lost after menopause. The effects of oestrogens are mediated by the activation of nuclear receptors (ERα and ERβ) and by the G protein-coupled oestrogen receptor (GPER). This study aims to evaluate the potential role of GPER in coronary circulation in female and male rats. The baseline coronary perfusion pressure (CPP) and the concentration–response curve with a GPER agonist (G-1) were evaluated in isolated hearts before and after the blockade of GPER. GPER, superoxide dismutase (SOD-2), catalase and gp91phox protein expression were assessed by Western blotting. Superoxide production was evaluated ‘in situ’ via dihydroethidium fluorescence (DHE). GPER blockade significantly increased the CPP in both groups, demonstrating the modulation of coronary tone by GPER. G-1 causes relaxation of the coronary bed in a concentration-dependent manner and was significantly h...
Hypertension, 2007
This study investigated the contribution of estrogen receptors (ERs) ␣ and  for epicardial coronary artery function, vascular NO bioactivity, and superoxide (O 2 Ϫ ) formation. Porcine coronary rings were suspended in organ chambers and precontracted with prostaglandin F 2␣ to determine direct effects of the selective ER agonists 4,4Ј,4Љ-(4-propyl-[ 1 H]pyrazole-1,3,5-triyl)tris-phenol (PPT) or 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN) or the nonselective ER agonist 17-estradiol. Indirect effects on contractility to U46619 and relaxation to bradykinin were assessed and effects on NO, nitrite, and O 2 Ϫ formation were measured in cultured cells. Within 5 minutes, selective ER␣ activation by PPT, but not 17-estradiol or the ER agonist DPN, caused rapid, NO-dependent, and endotheliumdependent relaxation (49Ϯ5%; PϽ0.001 versus ethanol). PPT also caused sustained endothelium-and NO-independent vasodilation similar to 17-estradiol after 60 minutes (72Ϯ3%; PϽ0.001 versus ethanol). DPN induced endotheliumdependent NO-independent relaxation via endothelium-dependent hyperpolarization (40Ϯ4%; PϽ0.01 versus ethanol). 17-Estradiol and PPT, but not DPN, attenuated the responses to U46619 and bradykinin. All of the ER agonists increased NO and nitrite formation in vascular endothelial but not smooth muscle cells and attenuated vascular smooth muscle cell O 2