G protein-coupled estrogen receptor inhibits vascular prostanoid production and activity

Abstract

Complications of atherosclerotic vascular disease, such as myocardial infarction and stroke, are the most common cause of death in postmenopausal women. Endogenous estrogens inhibit vascular inflammation-driven atherogenesis, a process that involves cyclooxygenase-derived vasoconstrictor prostanoids such as thromboxane A2. Here, we studied whether the G protein-coupled estrogen receptor (GPER) mediates estrogen-dependent inhibitory effects on prostanoid production and activity under pro-inflammatory conditions. Effects of estrogen on production of thromboxane A2 were determined in human endothelial cells stimulated by the pro-inflammatory cytokine TNF-α. Moreover, Gper-deficient (Gper−/−) and wild-type mice were fed a pro-inflammatory diet and underwent ovariectomy or sham surgery to unmask the role of endogenous estrogens. Thereafter, endothelium-dependent contractions to acetylcholine-stimulated vasoconstrictor prostanoids and the thromboxane-prostanoid receptor agonist U46619 were recorded in isolated carotid arteries. In endothelial cells, TNF-α-stimulated thromboxane A2 production was inhibited by estrogen, an effect blocked by the GPER-selective antagonist G36. In ovary-intact mice, deletion of Gper increased prostanoid-dependent contractions by 2-fold. Ovariectomy also augmented prostanoid-dependent contractions by 2-fold in wild-type mice, but had no additional effect in Gper−/− mice. These contractions were blocked by the cyclooxygenase inhibitor meclofenamate and unaffected by the nitric oxide synthase inhibitor L-NAME. Vasoconstrictor responses to U46619 did not differ between groups, indicating intact signaling downstream of thromboxane-prostanoid receptor activation. In summary, under pro-inflammatory conditions, estrogen inhibits vasoconstrictor prostanoid production in endothelial cells and activity in intact arteries through GPER. Selective activation of GPER may therefore be considered as a novel strategy to treat increased prostanoid-dependent vasomotor tone or vascular disease in postmenopausal women.

GPER–novel membrane oestrogen receptor

“…GPER-deficient mice have enhanced prostanoid production and vasoconstriction (42, 43) and elevated responses to endothelin-1 in carotid arteries (44). The GPER agonist G-1 attenuates coronary artery contractions to endothelin-1 to the same extent as the GPER agonist and ERα/ERβ antagonist ICI 182,780 further demonstrating the independent actions of this membrane receptor in vessel function (37).…”

Mechanisms underlying the influence of oestrogen on cardiovascular physiology in women

“…GPER also mediates oestrogen‐dependent inhibition of endothelium‐derived vasoconstrictor prostanoid production and activity under pro‐inflammatory conditions, providing evidence for a novel mechanism through which GPER could inhibit vascular tone and inflammation (Meyer et al . ).…”

“…Apart from this, ERβ has also been associated with COX-2 expression and both PGI 2 and TXA 2 concentrations at basal state, which suggests the possibility of a ligand-independent regulation of COX-2 activity and PGH 2 substrate availability (Su et al 2009). GPER also mediates oestrogen-dependent inhibition of endothelium-derived vasoconstrictor prostanoid production and activity under pro-inflammatory conditions, providing evidence for a novel mechanism through which GPER could inhibit vascular tone and inflammation (Meyer et al 2015).…”

GPCRs in context: sexual dimorphism in the cardiovascular system

“…Oestrogens have broad effects on the biosynthesis of prostanoids, including decreasing activity of COX‐1 and COX‐2. There is evidence that many of these actions are mediated by GPER, as it inhibits prostanoid production and activity (Meyer et al ., ), while loss of GPER is associated with increased endothelial prostanoid‐mediated vasoconstriction and increases in TP receptor‐mediated contractions (Meyer et al ., ). In the CVS, the prostanoid receptors producing significant sexually dimorphic phenotypes are the TP, IP and EP receptors, discussed below.…”