ET_B receptor-mediated vasodilation is regulated by estradiol in young women

The endothelin-B (ET_B) receptor is a key regulator of vascular endothelial function in women. We have previously shown that the ET_B receptor mediates vasodilation in young women, an effect that is lost after menopause. However, the direct impact of changes in estradiol (E₂) on ET_B receptor function in women remains unclear. Therefore, the purpose of this study was to test the hypothesis that E₂ exposure modulates ET_B receptor-mediated dilation in young women. Fifteen young women (24 ± 4 yr, 24 ± 3 kg/m²) completed the study. Endogenous sex hormone production was suppressed with daily administration of a gonadotropin-releasing hormone antagonist (GnRHant; Ganirelix) for 10 days; E₂ (0.1 mg/day, Vivelle-Dot patch) was added back on days 4-10. We measured vasodilation in the cutaneous microcirculation (microvascular endothelial function) via local heating (42°C) on day 4 (GnRHant) and day 10 (GnRHant + E₂) using laser Doppler flowmetry coupled with intradermal microdialysis during perfusions of lactated Ringer's (control) and ET_B receptor antagonist (BQ-788, 300 nM). During GnRHant, vasodilatory responses to local heating were enhanced with ET_B receptor blockade (control: 83 ± 9 vs. BQ-788: 90 ± 5%CVC_max, P = 0.004). E₂ administration improved vasodilation in the control site (GnRHant: 83 ± 9 vs. GnRHant + E₂: 89 ± 8%CVC_max, P = 0.036). Furthermore, cutaneous vasodilatory responses during ET_B receptor blockade were blunted after E₂ administration (control: 89 ± 8 vs. BQ-788: 84 ± 8%CVC_max, P = 0.047). These data demonstrate that ovarian hormones, specifically E₂, modulate ET_B receptor function and contribute to the regulation of microvascular endothelial function in young women.NEW & NOTEWORTHY The endothelin-B (ETB) receptor mediates vasodilation in young women, an effect lost following menopause. It is unclear whether these alterations are due to aging or changes in estradiol (E2). During endogenous hormone suppression (GnRH antagonist), blockade of ETB receptors enhanced cutaneous microvascular vasodilation. However, during E2 administration, blockade of ETB receptors attenuated vasodilation, indicating that the ETB receptor mediates dilation in the presence of E2. In young women, ETB receptors mediate vasodilation in the presence of E2, an effect that is lost when E2 is suppressed.