Vascular endothelial estrogen receptor alpha is modulated by estrogen status and related to endothelial function and endothelial nitric oxide synthase in healthy women

Abstract

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.

Figure 1

ERα protein expression in endothelial cells collected during the EF and LF phases of the menstrual cycle in premenopausal women and in estrogen-deficient postmenopausal women. Values are mean ± se. Representative immunofluorescent images from a premenopausal woman measured during the EF and LF phases of the menstrual cycle and a postmenopausal woman are shown. *, P < 0.001 vs. LF.

Figure 2

Representative immunofluorescent images of eNOS and phosphorylated-eNOS-Ser1177 (Pe-NOS) proteins from a premenopausal woman and a postmenopausal woman.

Figure 3

Relation between EDD and ERα expression in vascular endothelial cells obtained from premenopausal (open circles) and postmenopausal women (solid circles). Each symbol represents the response of an individual woman.

Figure 4

Relation between eNOS (A) and phosphorylated-eNOS-Ser1177 (Pe-NOS) (B) and ERα expression in vascular endothelial cells obtained from premenopausal (open circles) and postmenopausal women (solid circles). Each symbol represents the response of an individual woman.