Vascular Endothelial Estrogen Receptor α Is Modulated by Estrogen Status and Related to Endothelial Function and Endothelial Nitric Oxide Synthase in Healthy Women

Context and Objective: Estrogen receptor alpha (ER alpha), a potent transcription factor expressed in vascular endothelial cells, plays a key role in regulating vascular function and health. We determined whether vascular endothelial cell expression of ER alpha is influenced by estrogen status and is related to vascular endothelial function in healthy women. Methods: ER alpha protein expression was measured (quantitative immunofluorescence) in endothelial cells from peripheral veins of 16 healthy, premenopausal women during the early follicular (EF) and late follicular (LF) phases of the menstrual cycle and 17 estrogen-deficient postmenopausal women. Endothelial-dependent dilation (EDD; brachial artery flow-mediated dilation) and endothelial nitric oxide synthase (eNOS) expression and activation were also measured in a subgroup of women. Results: In premenopausal women (n = 10), ER alpha expression was 30% lower (P < 0.001) during the EF (low estrogen) compared with the LF (high estrogen) phase of the menstrual cycle. In postmenopausal women, ER alpha expression was 33% lower (P < 0.001) compared with the LF phase of the menstrual cycle in premenopausal women. ER alpha expression was strongly related (r = 0.67; P < 0.001) to EDD, which was reduced in postmenopausal women. ER alpha abundance was positively related to expression of eNOS (r = 0.54; P = 0.009; n = 21) and ser1177 phosphorylated eNOS (r = 0.59; P = 0.006; n = 20). Conclusions: These results provide the first evidence that expression of ER alpha in vascular endothelial cells is modulated by estrogen status and may be a key determinant of vascular endothelial function in healthy pre- and postmenopausal women. ER alpha expression may influence vascular endothelial function in women by affecting protein levels and activation of eNOS. (J Clin Endocrinol Metab 94: 3513-3520, 2009)