ET‐1 Receptor Function in Women with Advancing Reproductive Age

Abstract

Endothelin‐1 (ET‐1) contributes to endothelial dysfunction, a primary driver of hypertension and cardiovascular disease. Our lab has previously shown that the ETB receptor mediates vasodilation in premenopausal women (PRE), but this effect is lost in postmenopausal women (POST). Noticeable declines in endothelial function are evident early in the menopausal transition, but the function of the ETB receptor in perimenopausal women (PERI) is unclear.PURPOSEThe purpose of this study was to test the hypothesis that ETB‐mediated vasodilation progressively declines with advancing reproductive age in women.METHODSWe used the STRAW+10 staging criteria to classify women as PRE (n=12, 26±2 yrs, 23±1 kg/m2, 83±2 mmHg), PERI (n=9, 50±1 yrs, 24±1 kg/m2, 84±3 mmHg), or POST (n=11, 56±1 yrs, 24±1 kg/m2, 87±2 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.RESULTSPRE showed the greatest cutaneous vasodilation in response to local heating (PRE: 93±2; PERI: 84±2; POST: 88±2 %CVC max, P<0.05 vs PERI and POST). There was a trend for increased vasodilatory responses to ETB receptor blockade with advancing reproductive age (PRE: 85±3; PERI: 91±2; POST: 92±3 %CVC max, P=0.13). However, there were no differences in vasodilatory responses during ETA receptor blockade (PRE: 90±2; PERI: 91±3; POST: 92±3 %CVC max, P=0.84). Finally, brachial artery flow‐mediated dilation tended to decline (PRE: 7±1; PERI: 6±1; POST: 5±1 %Δ, P=0.09) while pulse wave velocity increased with advancing reproductive age (PRE: 6±0; PERI: 7±0; POST: 7±0 m/s, P<0.05 vs PERI and POST).CONCLUSIONSThese preliminary data suggest that adverse changes in vascular function, and potentially ETB receptor function, are evident early in PERI. Therefore, future research examining the role of the ET‐1 pathway in progressive vascular dysfunction throughout the menopausal transition is warranted.Support or Funding InformationNIH R01 HL 146558, P20 GM 113125