ET‐1 Receptor Function in Women of Different Reproductive Age but Similar Chronological Age

Abstract

Endothelial dysfunction is a primary driver of hypertension and cardiovascular disease. Our lab has previously shown that endothelin-1 (ET-1), which contributes to endothelial dysfunction, is regulated by changes in ovarian hormones in premenopausal women (PRE). Additionally, while the ETB receptor mediates vasodilation in PRE, this effect is lost in postmenopausal women. However, the influence of reproductive aging, independent of chronological aging, on the function of the ETB receptor is unclear. Purpose The purpose of this study was to test the hypothesis that ETB-mediated vasodilation is progressively reduced with advancing reproductive age in women who are of similar chronological age. Methods We used the STRAW+10 staging criteria to classify women as PRE (n=4, 47±1 yrs, 26±1 kg/m2, 81±4 mmHg), early perimenopausal (PERI) (n=6, 49±1 yrs, 25±1 kg/m2, 79±3 mmHg), or late PERI (n=9, 49±1 yrs, 23±1 kg/m2, 81±3 mmHg). Cutaneous vasodilatory responses to local heating were measured using laser doppler flowmetry during microdialysis perfusions of lactated Ringer's (Control), ETB receptor blockade (BQ-788, 300nM), and ETA receptor blockade (BQ-123, 500nM). Cutaneous vascular conductance (CVC) was calculated during the plateau phase of local heating (42°C), and normalized to maximal vasodilation achieved by perfusion of sodium nitroprusside (28mM) and heating to 43°C. One-way ANOVAs were used to compare vasodilatory responses between groups with Tukey post-hoc tests. Data are presented as mean±SEM. Results By design, women were of similar chronological age (P=0.25) but at different reproductive stages. PRE showed the greatest cutaneous vasodilation in response to local heating (PRE: 93±4; early PERI: 80±2; late PERI: 90±3 %CVC max, P<0.05 vs early PERI). However, there were no differences in vasodilatory responses during ETB receptor blockade (PRE: 85±11; early PERI: 87±4; late PERI: 94±1 %CVC max, P=0.38) or ETA receptor blockade (PRE: 81±2; early PERI: 90±1; late PERI: 88±5 %CVC max, P=0.27) between groups. Conclusions These preliminary data suggest that microvascular endothelial function is reduced in early PERI, independent of chronological aging. Additionally, these preliminary comparisons suggest ETB-mediated vasodilation may not differ between PRE, early PERI, and late PERI. Still, future studies should repeat these measurements and correlate findings with concurrent measurements of ovarian hormones.