Abstract 071: Endothelin-1 Contributes to Vascular Dysfunction in Peri-Menopausal Women

Abstract

Declines in vascular function occur early in the menopausal transition, as previously demonstrated by a reduction in endothelial function in perimenopausal women (PERI). However, the mechanisms contributing to this decline remain to be elucidated. We have previously shown that vascular impairments in postmenopausal women (POST) are due in part to endothelin-1 (ET-1). Thus, the purpose of this study is to determine if ET-1 contributes to reductions in vascular function across the stages of the menopausal transition. We hypothesized plasma ET-1 levels would be elevated across menopausal stages, and negatively associated with endothelial function. We further hypothesized that ETB receptors would contribute to impaired vascular function in PERI. Methods: We measured vascular endothelial function (flow-mediated dilation, FMD) and plasma ET-1 in 180 women classified as premenopausal (PRE, n=33, 33±7 years), early PERI (n=20, 50±3 years), late PERI (n=25, 50±4 years), early POST (n=36, 55±3 years), and late POST (n=58, 60±4 years) based on the STRAW criteria. In a separate, secondary study, we measured cutaneous microvascular endothelial function via local heating during microdialysis perfusions of lactated Ringers (control) or ETB receptor antagonist (BQ-788, 300 nM) in 6 PRE (22±2 years) and 8 PERI (50±3 years). Results: Plasma ET-1 concentration increased in a step-wise fashion across menopausal stage (PRE 5.4±1.1, early PERI 5.8±1.0, late PERI 6.1±1.6, early POST 6.4±1.6, late POST 6.4±1.5 pg/mL; P<0.01). Furthermore, there was a significant inverse correlation between plasma ET-1 and brachial artery FMD (r=0.28; P<0.001). In our secondary study, cutaneous microvascular vasodilation was lower in PERI compared to PRE (82±7 vs 92±8 %CVCmax, P <0.05). In PRE, ETB receptor blockade mediated dilation (control: 92±8 vs ETB: 83±9 %CVCmax, P <0.05), however this effect was lost in PERI (82±7 vs 92±4 %CVCmax, P <0.05). Conclusions: These data suggest that elevated ET-1 contributes to impairments in vascular endothelial function across the menopausal transition. Furthermore, the decline in endothelial function is evident in the macro- and micro- circulation during the perimenopausal transition, due in part to a loss of ETB mediated dilation.