Endothelial Estrogen Receptor α/β Protein Ratio is Associated with Circulating Estrogen Levels in Healthy Women

Abstract

OBJECTIVEVascular aging, featuring endothelial dysfunction, precedes an increased risk of cardiovascular disease (CVD). The menopause transition (i.e., perimenopause) is characterized by changes in ovarian hormone and vascular health. We previously reported a decline in endothelial function that was correlated with lower estradiol (E2) and estrone levels. Biological effects of E2 on endothelial function are mediated via estrogen receptors (ER). We determined whether ER α and β activation (i.e. nuclear translocation) and the ER α/β ratio in endothelial cell (EC)s differed by menopause stages and whether they were associated with reduced endothelial function across menopause stages.METHODSEC samples were harvested from 67 healthy, fasted women (aged 30–70 years) classified as premenopausal (Pre; regular menstrual cycles; n=15, 33±6yrs; mean±SD), early perimenopausal (EPeri; > 2 cycles with cycle length changes of ≥7 days; n=15, 49±3yrs), late perimenopausal (LPeri; ≥2 but <12 months of amenorrhea; n=17, 49±4yrs), or postmenopausal (Post; n=20, 56±5yrs). ECs were analyzed for whole cell and nuclear ER α and β protein content by immunofluorescence. Endothelial‐dependent vasodilation was measured by brachial artery flow‐mediated dilation (FMD) using ultrasound.RESULTSERα nuclear/cell protein ratio (a surrogate marker of nuclear translocation) was lower (p<0.01) in EPeri compared to other menopause stages; ERβ nuclear/cell protein ratio showed a similar trend (p=0.07). ER α/β protein ratio in whole cell showed no difference across stages, but was correlated with serum E2 (r=0.30, p=0.08) and estrone (r=0.38, p=0.03) across menopause stages. FMD was not correlated with any ER protein data.CONCLUSIONThe menopause transition, specifically the early perimenopausal period, may be a vulnerable period for the decline of endothelial ER α and β activation; however, we failed to show any correlation between endothelial function and ER protein content. Whether the decline in endothelial ER function/activity contributes to vascular dysfunction warrants further study.Support or Funding InformationNIH R01AG049762, R01AG027678, R56HL114073, P30DK048520, P50HD073063, NCATS Colorado CTSA UL1TR001082, and Eastern Colorado VA GRECCThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.