Matthias R. Meyer

Regulatory Role of G Protein–Coupled Estrogen Receptor for Vascular Function and Obesity

We found that the selective stimulation of the intracellular, transmembrane G protein-coupled estrogen receptor (GPER), also known as GPR30, acutely lowers blood pressure after infusion in normotensive rats and dilates both rodent and human arterial blood vessels. Stimulation of GPER blocks vasoconstrictor-induced changes in intracellular calcium concentrations and vascular tone, as well as serum-stimulated cell proliferation of human vascular smooth muscle cells. Deletion of the GPER gene in mice abrogates vascular effects of GPER activation and is associated with visceral obesity. These findings suggest novel roles for GPER in protecting from cardiovascular disease and obesity.

Obesity, insulin resistance and diabetes: sex differences and role of oestrogen receptors

Obesity increases the risk of coronary artery disease through insulin resistance, diabetes, arterial hypertension and dyslipidemia. The prevalence of obesity has increased worldwide and is particularly high among middle‐aged women and men. After menopause, women are at an increased risk to develop visceral obesity due to the loss of endogenous ovarian hormone production. Effects of oestrogens are classically mediated by the two nuclear oestrogen receptors (ERs) α and β. In addition, more recent research has shown that the intracellular transmembrane G‐protein‐coupled oestrogen receptor (GPER) originally designated as GPR30 also mediates some of the actions attributed to oestrogens. Oestrogen and its receptors are important regulators of body weight and insulin sensitivity not only in women but also in men as demonstrated by ER mutations in rodents and humans. This article reviews the role of sex hormones and ERs in the context of obesity, insulin sensitivity and diabetes as well as the related clinical issues in women and men.

Differential Effects of 17β-Estradiol on Function and Expression of Estrogen Receptor α, Estrogen Receptor β, and GPR30 in Arteries and Veins of Patients With Atherosclerosis

Venous complications have been implicated in the adverse effects of hormone replacement therapy. This study investigated acute effects of the natural estrogen, 17&bgr;-estradiol, on function, estrogen receptors/GPR30 expression, and kinase activation in vascular rings and cultured smooth muscle cells from arteries and veins of patients with coronary artery disease. Changes in vascular tone of internal mammary arteries and saphenous veins exposed to the steroid were recorded. 17&bgr;-Estradiol caused concentration-dependent, endothelium-independent relaxation in arteries (P<0.05 versus solvent control) but not in veins (P not significant). 17&bgr;-Estradiol enhanced contractions to endothelin-1 in veins but not in arteries. The novel membrane estrogen receptor GPR30 was detected in both vessels. Moreover, gene expression of estrogen receptor &bgr; was 10-fold higher than that of estrogen receptor &agr; or GPR30 (P<0.05). Expression of all 3 of the receptors was reduced after exposure to 17&bgr;-estradiol in arteries but not in veins (P<0.05). Basal phosphorylation levels of extracellular signal-regulated kinase were higher in venous than in arterial smooth muscle cells and were increased by 17&bgr;-estradiol in arterial cells only. In summary, this is the first study to report that, in human arteries but not in veins, 17&bgr;-estradiol acutely affects vascular tone, estrogen receptor expression, including GPR30, and extracellular signal-regulated kinase phosphorylation. These data indicate that effects of natural estrogens in humans differ between arterial and venous vascular beds, which may contribute to the vascular risks associated with menopause or hormone therapy.

Postmenopausal Hypertension Mechanisms and Therapy

Hypertension in women is often undiagnosed or inadequately treated, especially after menopause when cardiovascular risk increases. In premenopausal women, endogenous estrogens maintain vasodilation and thus contribute to blood pressure control. Aging and the loss of endogenous estrogen production after menopause are accompanied by increases in blood pressure, contributing to the high prevalence of hypertension in older women. Currently, ≈75% of postmenopausal women in the United States are hypertensive. The high prevalence of obesity, the lack of regular physical exercise, and dietary salt are important factors contributing to and aggravating postmenopausal hypertension. In view of the ongoing population aging throughout the world, diagnosis and treatment of hypertension in postmenopausal women are important to reduce the excess burden of associated cardiovascular disease and to improve outcomes of potentially fatal complications such as stroke and myocardial infarction. This article discusses current knowledge about the mechanisms and therapeutic issues related to postmenopausal hypertension. More than 25% of the female adult world population is hypertensive.1 Elevations in blood pressure in women are related to cardiovascular risk (Figure, panel A),2,3 with the prevalence of hypertension being particularly high among women aged ≥60 years.1 In the United States, ≈75% of postmenopausal women are hypertensive.4 Hypertension is often accompanied by other cardiovascular risk factors, eg, obesity, dyslipidemia, and diabetes mellitus.5 It is noteworthy that the prevalence of hypertension-related cardiovascular complications is greater in postmenopausal women than in age-matched men.6 Indeed, these complications represent the leading cause of death in women.6 Figure. A, Cumulative incidence of cardiovascular events in women without hypertension, according to blood pressure category at the baseline examination. Vertical bars indicate 95% CIs. According to earlier classifications from the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, optimal blood …

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

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.

Non-genomic regulation of vascular cell function and growth by estrogen

Estrogens exert rapid, non-genomic effects, which are mediated by plasma membrane-associated estrogen receptors (mER) mERalpha and mERbeta, and the intracellular transmembrane G protein-coupled estrogen receptor (GPER). Membrane-initiated responses contribute to transcriptional activation, resulting in a complex interplay of nuclear and extra-nuclear mechanisms that mediate the acute physiological responses to estrogens. Non-genomic estrogen signaling also activates a variety of intracellular estrogen signaling pathways that regulate vascular function and cell growth involving rapid but also long-term effects. This review discusses recent advances in understanding of the mechanisms of non-genomic estrogen receptor signaling in the vascular wall.

Dilation of Epicardial Coronary Arteries by the G Protein-Coupled Estrogen Receptor Agonists G-1 and ICI 182,780

Endogenous estrogens protect from coronary artery disease in premenopausal women, but the mechanisms involved are only partly understood. This study investigated whether activation of the novel G protein-coupled estrogen receptor (GPER, formerly known as GPR30) affects coronary artery tone, and whether this is affected by concomitant blockade of estrogen receptors (ER) α and β. Rings of epicardial porcine coronary arteries suspended in organ chambers were precontracted with prostaglandin F2α, and direct effects of G-1 (GPER agonist) and ICI 182,780 (GPER agonist and ERα/ERβ antagonist) were determined. In addition, indirect effects on contractility to endothelin-1 and serotonin (a vasoconstrictor released from aggregating platelets during acute myocardial infarction) were assessed. ICI 182,780 and G-1 caused acute dilation of coronary arteries to a comparable degree (p < 0.05 vs. solvent control). Both GPER agonists attenuated contractions to endothelin-1 (p < 0.05 vs. ethanol), but not to serotonin (n.s.). In summary, these findings provide evidence for direct and indirect coronary artery dilator effects of GPER independent of ERα and ERβ, and are the first demonstration of arterial vasodilation in response to ICI 182,780.

Obesity and risk of vascular disease: importance of endothelium-dependent vasoconstriction

Obesity has become a serious global health issue affecting both adults and children. Recent devolopments in world demographics and declining health status of the worlds population indicate that the prevalence of obesity will continue to increase in the next decades. As a disease, obesity has deleterious effects on metabolic homeostasis, and affects numerous organ systems including heart, kidney and the vascular system. Thus, obesity is now regarded as an independent risk factor for atherosclerosis‐related diseases such as coronary artery disease, myocardial infarction and stroke. In the arterial system, endothelial cells are both the source and target of factors contributing to atherosclerosis. Endothelial vasoactive factors regulate vascular homeostasis under physiological conditions and maintain basal vascular tone. Obesity results in an imbalance between endothelium‐derived vasoactive factors favouring vasoconstriction, cell growth and inflammatory activation. Abnormal regulation of these factors due to endothelial cell dysfunction is both a consequence and a cause of vascular disease processes. Finally, because of the similarities of the vascular pathomechanisms activated, obesity can be considered to cause accelerated, ‘premature’ vascular aging. Here, we will review some of the pathomechanisms involved in obesity‐related activation of endothelium‐dependent vasoconstriction, the clinical relevance of obesity‐associated vascular risk, and therapeutic interventions using ‘endothelial therapy’ aiming at maintaining or restoring vascular endothelial health.

G Protein-coupled Estrogen Receptor Protects from Atherosclerosis

Coronary atherosclerosis and myocardial infarction in postmenopausal women have been linked to inflammation and reduced nitric oxide (NO) formation. Natural estrogen exerts protective effects on both processes, yet also displays uterotrophic activity. Here, we used genetic and pharmacologic approaches to investigate the role of the G protein-coupled estrogen receptor (GPER) in atherosclerosis. In ovary-intact mice, deletion of gper increased atherosclerosis progression, total and LDL cholesterol levels and inflammation while reducing vascular NO bioactivity, effects that were in some cases aggravated by surgical menopause. In human endothelial cells, GPER was expressed on intracellular membranes and mediated eNOS activation and NO formation, partially accounting for estrogen-mediated effects. Chronic treatment with G-1, a synthetic, highly selective small molecule agonist of GPER, reduced postmenopausal atherosclerosis and inflammation without uterotrophic effects. In summary, this study reveals an atheroprotective function of GPER and introduces selective GPER activation as a novel therapeutic approach to inhibit postmenopausal atherosclerosis and inflammation in the absence of uterotrophic activity.

Deletion of G Protein–Coupled Estrogen Receptor Increases Endothelial Vasoconstriction

Endogenous estrogens mediate protective effects in the cardiovascular system, affecting both endothelium-dependent and endothelium-independent mechanisms. Previous studies have suggested that nonselective estrogen receptor agonists such as endogenous estrogens inhibit endothelium-dependent vasoconstriction; however, the role of estrogen receptors in this response has not yet been clarified. This study investigated whether the intracellular transmembrane G protein–coupled estrogen receptor (GPER) regulates vascular reactivity in mice. Effects of chronic deficiency (using mice lacking the GPER gene) and acute inhibition (using the GPER-selective antagonist G15) on endothelium-dependent and endothelium-independent vascular reactivity, and the effects of GPER deficiency on vascular gene expression and structure were investigated. We found that chronic GPER deficiency is associated with increased endothelial prostanoid-mediated vasoconstriction but has no effect on endothelial nitric oxide bioactivity, gene expression of endothelial nitric oxide synthase and thromboxane prostanoid (TP) receptor, or vascular structure. GPER deletion also increases TP receptor–mediated contraction. Acute GPER blockade enhances endothelium-dependent contractions and reduces endothelial nitric oxide bioactivity. Contractions in response to TP receptor activation are unaffected by G15. In conclusion, this study identifies GPER as the first estrogen receptor with inhibitory activity on endothelium-dependent contractility. These findings may be important for understanding and treating diseases associated with increased endothelial vasoconstrictor prostanoid activity such as hypertension and obesity.