Activation of G protein-coupled estrogen receptor induces endothelium-independent relaxation of coronary artery smooth muscle.
ABSTRACT Estrogens can either relax or contract arteries via rapid, nongenomic mechanisms involving classic estrogen receptors (ER). In addition to ERα and ERβ, estrogen may also stimulate G protein-coupled estrogen receptor 1 (GPER) in nonvascular tissue; however, a potential role for GPER in coronary arteries is unclear. The purpose of this study was to determine how GPER activity influenced coronary artery reactivity. In vitro isometric force recordings were performed on endothelium-denuded porcine arteries. These studies were augmented by RT-PCR and single-cell patch-clamp experiments. RT-PCR and immunoblot studies confirmed expression of GPER mRNA and protein, respectively, in smooth muscle from either porcine or human coronary arteries. G-1, a selective GPER agonist, produced a concentration-dependent relaxation of endothelium-denuded porcine coronary arteries in vitro. This response was attenuated by G15, a GPER-selective antagonist, or by inhibiting large-conductance calcium-activated potassium (BK(Ca)) channels with iberiotoxin, but not by inhibiting NO signaling. Last, single-channel patch-clamp studies demonstrated that G-1 stimulates BK(Ca) channel activity in intact smooth muscle cells from either porcine or human coronary arteries but had no effect on channels isolated in excised membrane patches. In summary, GPER activation relaxes coronary artery smooth muscle by increasing potassium efflux via BK(Ca) channels and requires an intact cellular signaling mechanism. This novel action of estrogen-like compounds may help clarify some of the controversy surrounding the vascular effects of estrogens.
- SourceAvailable from: Ramón A Lorca[Show abstract] [Hide abstract]
ABSTRACT: The large-conductance voltage- and Ca(2+)-activated K(+) channel (BKCa) is an important regulator of membrane excitability in a wide variety of cells and tissues. In myometrial smooth muscle, activation of BKCa plays essential roles in buffering contractility to maintain uterine quiescence during pregnancy and in the transition to a more contractile state at the onset of labor. Multiple mechanisms of modulation have been described to alter BKCa channel activity, expression, and cellular localization. In the myometrium, BKCa is regulated by alternative splicing, protein targeting to the plasma membrane, compartmentation in membrane microdomains, and posttranslational modifications. In addition, interaction with auxiliary proteins (i.e., β1- and β2-subunits), association with G-protein coupled receptor signaling pathways, such as those activated by adrenergic and oxytocin receptors, and hormonal regulation provide further mechanisms of variable modulation of BKCa channel function in myometrial smooth muscle. Here, we provide an overview of these mechanisms of BKCa channel modulation and provide a context for them in relation to myometrial function.Frontiers in physiology. 01/2014; 5:289.
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ABSTRACT: Coronary heart disease (CHD) continues to be the greatest mortality risk factor in the developed world. Estrogens are recognized to have great therapeutic potential to treat CHD and other cardiovascular diseases; however, a significant array of potentially debilitating side effects continues to limit their use. Moreover, recent clinical trials have indicated that long-term postmenopausal estrogen therapy may actually be detrimental to cardiovascular health. An exciting new development is the finding that the more recently discovered G-protein-coupled estrogen receptor (GPER) is expressed in coronary arteries-both in coronary endothelium and in smooth muscle within the vascular wall. Accumulating evidence indicates that GPER activation dilates coronary arteries and can also inhibit the proliferation and migration of coronary smooth muscle cells. Thus, selective GPER activation has the potential to increase coronary blood flow and possibly limit the debilitating consequences of coronary atherosclerotic disease. This review will highlight what is currently known regarding the impact of GPER activation on coronary arteries and the potential signaling mechanisms stimulated by GPER agonists in these vessels. A thorough understanding of GPER function in coronary arteries may promote the development of new therapies that would help alleviate CHD, while limiting the potentially dangerous side effects of estrogen therapy.World journal of cardiology. 06/2014; 6(6):367-75.
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ABSTRACT: The presence of circulating plasma 17β-estradiol (E2) is beneficial in women against abnormal vascular tone development, such as coronary arterial vasospasms. Several vascular diseases have demonstrated that an increased expression of the sarcoplasmic reticulum Ca2+-ATPase pump (SERCA2b) serves to limit the excessive accumulation of intracellular Ca2+. Therefore, the hypothesis of this study was that E2 would increase SERCA2b expression in the coronary vasculature. Coronary arteries were dissected from hearts obtained from mature female pigs. Artery segments were cultured for 24 hrs in E2 (1 pM or 1 nM) and homogenized for Western blot analysis. E2 (1 nM) induced a ~ 50% increase in the immunoreactivity for SERCA2b. E2 also increased the protein expression of the known SERCA regulatory proteins, protein kinase A (PKA) and protein kinase G (PKG). The E2-induced increase in SERCA2b was attenuated when the culture media was supplemented with the α/β estrogen receptor antagonist, ICI 182,780, and the PKG antagonist, KT5823. The PKA antagonist (KT5720) had no effect on SERCA2b expression. Removal of the endothelium (using a wooden toothpick) decreased the E2-mediated increase in SERCA2b and PKG expression by 45% and 47%, respectively. Overall, these findings suggest that one of the potential cardiovascular benefits of E2 in women is the upregulation of SERCA2b, via the activation of the classical α and β estrogen receptor pathway.This article is protected by copyright. All rights reserved.Clinical and Experimental Pharmacology and Physiology 03/2014; · 2.41 Impact Factor