The Role of Estrogen Receptors in Cardiovascular Disease

Abstract

Cardiovascular Diseases (CVDs) are the leading cause of death globally. More than 17 million people die worldwide from CVD per year. There is considerable evidence suggesting that estrogen modulates cardiovascular physiology and function in both health and disease, and that it could potentially serve as a cardioprotective agent. The effects of estrogen on cardiovascular function are mediated by nuclear and membrane estrogen receptors (ERs), including estrogen receptor alpha (ERα), estrogen receptor beta (ERβ), and G-protein-coupled ER (GPR30 or GPER). Receptor binding in turn confers pleiotropic effects through both genomic and non-genomic signaling to maintain cardiovascular homeostasis. Each ER has been implicated in multiple pre-clinical cardiovascular disease models. This review will discuss current reports on the underlying molecular mechanisms of the ERs in regulating vascular pathology, with a special emphasis on hypertension, pulmonary hypertension, and atherosclerosis, as well as in regulating cardiac pathology, with a particular emphasis on ischemia/reperfusion injury, heart failure with reduced ejection fraction, and heart failure with preserved ejection fraction.

Keywords: GPR30; atherosclerosis; estrogen; estrogen receptor alpha; estrogen receptor beta; estrogen receptors; heart failure with preserved ejection fraction; heart failure with reduced ejection fraction; hypertension; ischemia-reperfusion injury.

Figure 1

The role of estrogen receptors in vascular disease: hypertension, pulmonary hypertension, and atherosclerosis. Depicted pathways have been shown to be involved in animal models of cardiovascular disease. CASMC: coronary artery smooth muscle cells; ERα: estrogen receptor alpha; ERβ: estrogen receptor beta; GPR30: G-protein-coupled estrogen receptor; Mig: migration; PASMC: pulmonary artery smooth muscle cells; Prolif: proliferation; RV: right ventricular; Vasc: vascular; VSMC: vascular smooth muscle cells; ↑: increased; ↓: decreased; ↕: conflicting results.

Figure 2

The role of estrogen receptors in heart disease: ischemia/reperfusion injury, heart failure with reduced ejection fraction, and heart failure with preserved ejection fraction. Depicted pathways have been shown to be involved in animal models of cardiovascular disease. EF: ejection fraction; ERα: estrogen receptor alpha; ERβ: estrogen receptor beta; GPR30: G-protein-coupled estrogen receptor; HFpEF: heart failure with preserved ejection fraction; HFrEF: heart failure with reduced ejection fraction; I/R injury: ischemia/reperfusion injury; ROS: reactive oxygen species; ↑: increased; ↓: decreased.