ETB Receptor Function is Modulated by Estradiol in Young Women

Abstract

It is well known that vascular endothelial function declines in women after menopause. Our laboratory has recently shown that impaired endothelial function in postmenopausal women is due in part to a loss of endothelin‐B (ETB) receptor mediated dilation. However, it is unclear whether these changes in ETB function are due to aging or menopause‐related declines in ovarian hormones. Therefore, the purpose of this study was to test the hypothesis that short‐term estradiol (E2) administration would enhance the contribution of ETB receptor mediated dilation during local heating in young women. Twelve young women (24 ± 4 years, 24 ± 3 kg/m2, mean arterial blood pressure: 84 ± 6 mm Hg) participated in this 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 cutaneous vasodilation to local heating (42°C) on day 4 (GnRHant) and day 10 (GnRHant+E2) via laser Doppler flowmetry coupled with intradermal microdialysis for the perfusion of lactated Ringer’s (control) and ETB receptor antagonist (BQ‐788, 300 nM). Cutaneous vascular conductance (CVC) was calculated as cutaneous red blood cell flux/mean arterial blood pressure, and expressed as a percent of maximal vasodilation (CVC %max) achieved with local heating to 43°C and perfusion of sodium nitroprusside (28 mM). E2 administration improved cutaneous vasodilation by 8 ± 10% (control site; P = 0.02) compared to GnRHant. ETB receptor blockade increased cutaneous vasodilation to local heating during hormone suppression with GnRHant (control: 84 ± 7 vs. BQ‐788: 89 ± 5 CVC %max, P = 0.02). However, ETB receptor blockade tended to reduce cutaneous vasodilation to local heating during short duration E2 administration (control: 90 ± 7 vs. BQ‐788: 85 ± 8 CVC %max, P = 0.08). These data indicate that suppression of endogenous ovarian hormone production alters ETB receptor responses in young women, mimicking the response profile in postmenopausal women observed in our previous data. Furthermore, these data suggest that E2 modulates ETB receptor function. Additional data are needed to determine ETB receptor function and sensitivity to E2 in postmenopausal women.Support or Funding InformationResearch supported by AHA Award 16SDG30700015 (MMW), NIH Grant U54‐GM104941 (PI: Binder‐Macleod), and P20 GM113125 (DGE).