17β-Estradiol modulates vasoconstriction induced by endothelin-1 following trauma-hemorrhage

Abstract

Although endothelin-1 (ET-1) induces vasoconstriction, it remains unknown whether 17␤-estradiol (E2) treatment following trauma-hemorrhage alters these ET-1-induced vasoconstrictive effects. In addition, the role of the specific estrogen receptor (ER) subtypes (ER-␣ and ER-␤) and the endothelium-localized downstream mechanisms of actions of E2 remain unclear. We hypothesized that E2 attenuates increased ET-1-induced vasoconstriction following trauma-hemorrhage via an ER-␤-mediated pathway. To study this, aortic rings were isolated from male SpragueDawley rats following trauma-hemorrhage with or without E2 treatment, and alterations in tension were determined in vitro. Doseresponse curves to ET-1 were determined, and the vasoactive properties of E2, propylpyrazole triol (PPT, ER-␣ agonist), and diarylpropionitrile (DPN, ER-␤ agonist) were determined. The results showed that trauma-hemorrhage significantly increased ET-1-induced vasoconstriction; however, administration of E2 normalized ET-1-induced vasoconstriction in trauma-hemorrhage vessels to the shamoperated control level. The ER-␤ agonist DPN counteracted ET-1-induced vasoconstriction, whereas the ER-␣ agonist PPT was ineffective. Moreover, the vasorelaxing effects of E2 were not observed in endothelium-denuded aortic rings or by pretreatment of the rings with a nitric oxide (NO) synthase inhibitor. Cyclooxygenase inhibition with indomethacin had no effect on the action of E2. Thus, E2 administration attenuates ET-1-induced vasoconstriction following trauma-hemorrhage via an ER-␤-mediated pathway that is dependent on endothelium-derived NO synthesis. estrogen receptor; nitric oxide; endothelium; aortic ring IT IS WELL ESTABLISHED THAT sex difference influences cardiovascular and immunological responsiveness via sex hormones, which have potent vasoactive properties (3,20,24,27,32,34). In this regard, the beneficial effects of 17␤-estradiol (E 2 ) administration have been demonstrated by improvement in organ perfusion and function under a range of conditions (3)(4)(5)25). These studies and others (3, 9, 11) have led to the development of the concept that treatment of male trauma victims with estrogenic compounds can alleviate or attenuate the physiological and immunological derangements associated with such injury.Estrogen can improve circulation via vasodilatation induced by either prostacyclin or nitric oxide (NO) synthesis and/or by decreasing the production of vasoconstrictor agents, such as endothelin or angiotensin II (4, 27, 30). ET-1 is a potent vasoactive peptide produced by vascular endothelial cells and exerts its vasoconstrictor effects locally on the underlying vascular smooth muscle cells (31). The effects of E 2 on ET-1-mediated vasoconstriction are mediated through downstream mechanisms that are induced by estrogen receptor (ER) activation. In this regard, two major subtypes of ERs have been identified, ER-␣ and ER-␤ (21, 35). Although studies have demonstrated that vascular endothelial cells and myocytes express both the ER-␣ and ER-␤ subtype...

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