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