Distinct Roles of Estrogen Receptors α and β Mediating Acute Vasodilation of Epicardial Coronary Arteries

Abstract

This study investigated the contribution of estrogen receptors (ERs) alpha and beta for epicardial coronary artery function, vascular NO bioactivity, and superoxide (O(2)(-)) formation. Porcine coronary rings were suspended in organ chambers and precontracted with prostaglandin F(2alpha) to determine direct effects of the selective ER agonists 4,4',4''-(4-propyl-[(1)H]pyrazole-1,3,5-triyl)tris-phenol (PPT) or 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN) or the nonselective ER agonist 17beta-estradiol. Indirect effects on contractility to U46619 and relaxation to bradykinin were assessed and effects on NO, nitrite, and O(2)(-) formation were measured in cultured cells. Within 5 minutes, selective ERalpha activation by PPT, but not 17beta-estradiol or the ERbeta agonist DPN, caused rapid, NO-dependent, and endothelium-dependent relaxation (49+/-5%; P<0.001 versus ethanol). PPT also caused sustained endothelium- and NO-independent vasodilation similar to 17beta-estradiol after 60 minutes (72+/-3%; P<0.001 versus ethanol). DPN induced endothelium-dependent NO-independent relaxation via endothelium-dependent hyperpolarization (40+/-4%; P<0.01 versus ethanol). 17beta-Estradiol and PPT, but not DPN, attenuated the responses to U46619 and bradykinin. All of the ER agonists increased NO and nitrite formation in vascular endothelial but not smooth muscle cells and attenuated vascular smooth muscle cell O(2)(-) formation (P<0.001). ERalpha activation had the most potent effects on both nitrite formation and inhibiting O(2)(-) (P<0.05). These data demonstrate novel and differential mechanisms by which ERalpha and ERbeta activation control coronary artery vasoreactivity in males and females and regulate vascular NO and O(2)(-) formation. The findings indicate that coronary vascular effects of sex hormones differ with regard to affinity to ERalpha and ERbeta, which will contribute to beneficial and adverse effects of hormone replacement therapy.

Estradiol selectively stimulates endothelial prostacyclin production through estrogen receptor-α

“…Moreover, E 2 has been reported to increase COX-1 expression through ERa in ovine endothelial cells transfected with the human COX-1 promoter (Gibson et al 2005). Our data describe for the first time an ERa-dependent increase of COX-1 expression in human cells, similar to that reported for other vascular enzymes responsible for vasodilator production, such as endothelial nitric oxide synthase (Traupe et al 2007).…”

“…Our results add new information that supports a role for ERa in E 2 -mediated vasodilatory effects. Therefore, E 2 stimulates not only nitric oxide production but also PGI2 production through ERa, via both genomic and non-genomic pathways (Chen et al 1999, Traupe et al 2007). In addition, ERa agonists have been shown to improve endothelial dysfunction in rat blood vessels (Widder et al 2003).…”

Selective estrogen receptor-α and estrogen receptor-β agonists rapidly decrease pulmonary artery vasoconstriction by a nitric oxide-dependent mechanism

“…The rapid onset of the ER-␣-and ER-␤-mediated decrease in PA vasoconstriction (Ͻ20 min for PE-induced vasoconstriction and Ͻ45 min for HPV) is suggestive of a nongenomic increase in NO release. The concentrations required to mediate these effects were similar to those reported by other investigators demonstrating vasorelaxation in isolated systemic arteries (6,36). Nongenomic signaling by estrogens appear to be particularly important in "nontraditional" sex hormone target tissues (12).…”

Estradiol Regulation of Prostanoids Production in Endothelium

“…But estradiol also indirectly affects vasoreactivity to contracting and relaxing substances. In epicardial porcine coronary arteries activation of ER , but not of ER , reduces thromboxane A 2 vasoconstriction, indicating another indirect and vasodilator function of ER (Traupe et al, 2007). Other data suggest that the estrogen-dependent constrictor prostanoid mechanism in the vascular wall may play an important role in the regulation of vascular tone in the female, in both normal and pathophysiological states.…”