The G protein-coupled estrogen receptor GPER/GPR30 as a regulator of cardiovascular function

Abstract

Endogenous estrogens are important regulators of cardiovascular homeostasis in premenopausal women and delay 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.

Figure 1

Proposed estrogen receptor (ER)-activated signaling pathways involved in vasodilation. 17β-Estradiol (E₂) can activate a subpopulation of ER at the plasma membrane (mER) that interacts with adaptor proteins (adaptor) and signaling molecules such as c-Src (1), which is critical for down-stream ER-induced signaling via PI₃K/Akt and MAPK pathways. E₂ also binds to the G protein-coupled estrogen receptor GPER, which is primarily localized to the endoplasmic reticulum (2). GPER activates downstream effectors, such as adenylate cyclase (resulting in cAMP production), and c-Src. c-Src, in turn, activates matrix metalloproteinases (MMP), which cleave pro-heparin-bound-epidermal growth factor receptors (EGFR). EGFR leads to multiple downstream events, including activation of MAPK and PI₃K. Once activated, PI₃K can induce NO generation by NO synthase (NOS) in vascular endothelial (eNOS) or smooth muscle cells (nNOS). Membrane permeant NO, in turn, activates guanylate cyclase (resulting in cGMP production). The NO/cGMP pathway is involved in acute vasodilator mechanisms, such as protein kinase G (PKG)-dependent regulation of myosin light chain phosphorylation, and activation of large-conductance calcium-activated potassium (BK_Ca) channels. E₂ also regulates cellular gene expression either via binding of ER dimers in the promotor region of target genes (3), through interaction of ER with other classes of transcription factors (TF) (4), or by regulation of TF phosphorylation (5). Target genes regulating vascular homeostasis include NOS and inflammatory cytokines. Adapted from Mol Cell Endocrinol, Vol. 308, Meyer, M.R., Haas, E., Prossnitz, E.R., Barton M, Non-genomic regulation of vascular cell function and growth by estrogen, Pages 9-16, ©2009, with permission from Elsevier.

Figure 2

Agonists and antagonists of GPER and plasma membrane-associated subpopulations of ERα and ERβ involved in rapid vascular estrogen signaling. Green arrows indicate activation, red arrows indicate inhibition, and the orange arrow indicates tissue-dependent activation or inhibition. SERM, selective estrogen receptor modulator; SERD, selective estrogen receptor downregulator.

Figure 3

GPER-dependent regulation of vascular tone. In precontracted carotid arteries from mice, the selective GPER-agonist G-1 (3 µM) causes acute dilation, which is even stronger than that of 17β-estradiol (E2, 3 µM, A). Dilatory effects of G-1 (3 µM) in carotid arteries of wild-type mice (GPER +/+) are absent in GPER-knockout animals (GPER −/−, B). Acute exposure to G-1 (3 µM) and the GPER agonist and ERα/ERβ antagonist ICI 182,780 (ICI, 3 µM) for 60 minutes evokes similar vasodilator responses of porcine epicardial coronary arteries (C). Intravenous injection of G-1 at increasing concentrations (4.12 ng/kg, 41.2 ng/kg, 412 ng/kg, and 20.6 µg/kg) acutely reduces mean arterial blood pressure (MAP) in normotensive rats. For comparison, the response to achetylcholine (ACh, 30 ng/kg) is shown (D). CTL, solvent control (ethanol 0.3%). Panels A, B, and D are reproduced from Haas, E., Bhattacharya, I., Brailoiu, E., Damjanovic, M., Brailoiu, G.C., Gao, X., Mueller-Guerre, L., Marjon, N.A., Gut, A., Minotti, R., Meyer, M.R., Amann, K., Ammann, E., Perez-Dominguez, A., Genoni, M., Clegg, D.J., Dun, N.J., Resta, T.C., Prossnitz, E.R., Barton, M., Regulatory role of G protein-coupled estrogen receptor for vascular function and obesity, Circ Res, 104(3), 288-291, ©2009 by the American Heart Association, with permission of the publisher. Panel C is adapted from Meyer, M.R., Baretella, O., Prossnitz, E.R., Barton, M., Dilation of epicardial coronary arteries by the G protein-coupled estrogen receptor agonists G-1 and ICI 182,780, Pharmacology, 86(1), 58-64, ©2010, with permission from S. Karger AG, Basel, Switzerland.

Figure 4

Sex-independent cardioprotective effects of GPER activation. Selective GPER activation by G-1 (110 nM, black bars) before global cardiac ischemia does not significantly alter heart rate (HR, A) and myocardial contractility (measured as left ventricular developed pressure, B) after 120 minutes of reperfusion in male and female rats compared to untreated controls (open bars). In contrast, G-1 treatment reduces postischemic contractive dysfunction (measured as rate pressure product, RPP, C) and infarct size (measured as percentage of the entire ventricular area, D). *P < 0.05 vs. same gender control. Adapted from Deschamps, A.M., Murphy, E, Am J Physiol Heart Circ Physiol, ©2009 by the American Physiological Society, used with permission.