Ovarian hormones modulate endothelin-1 receptor responses in young women
Date
2015
Authors
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Publisher
University of Delaware
Abstract
Cardiovascular disease is the leading cause of death in women. Endothelin-1 (ET-1) is a powerful vasoconstrictor released by the endothelium, which has been implicated in the development of endothelial dysfunction and CVD. ET-1 binds to two receptor subtypes, endothelin A (ET-A) and endothelin B (ET-B). Studies in animal and cell models indicate that ovarian hormones, such as estradiol (E2) and progesterone (P4), modulate ET-1 and its receptors. However, these mechanisms have not been thoroughly examined in humans. We hypothesized that ovarian hormones mediate microvascular vasodilation through an ET-B receptor mechanism. More specifically, we expected that estradiol up-regulates ET-B receptor expression on endothelial cells. During local skin warming, we used laser Doppler flowmetry coupled with intradermal microdialysis to measure skin microcirculatory responsiveness (% CVCmax) during ET-B antagonist infusion in women during their early follicular (EF) and mid-luteal (ML) phases ( n = 8; ages 19-22). We found that % CVCmax during heating tended to be lower in the ET-B blocked site compared to the control site during the ML phase (85.3% versus 90.0% CVCmax; p = 0.07), but not during the EF phase (90.7% versus 87.5% CVCmax; p = 0.22). This would suggest that ET-B receptors mediate vasodilation during the ML phase, when E2 and P4 are both elevated. Additionally, we treated human umbilical vein endothelial cells (HUVECs) with increasing doses of E2 for 24 hours and tested ET-B receptor expression with Western blot. We found no significant differences in ET-B receptor expression among any of the E2 doses (p = 0.7682). In summary, although acute E2 treatment did not alter ET-B receptor expression, our data suggest that chronic fluctuations in ovarian hormones during the menstrual cycle modulate ET-B receptor responses in women. Future studies both in young women and in our cell model will help to further elucidate the mechanism of action of E2 on ET-B receptor function and expression. This assessment of the endothelin system will continue to provide novel information on the mechanisms contributing to endothelial dysfunction in women, which will be particularly beneficial to women as they age and go through menopause.