Suppression by 17β-estradiol of monocyte adhesion to vascular endothelial cells is mediated by estrogen receptors

Abstract Several observational studies have shown that estrogen replacement therapy decreases cardiovascular mortality and morbidity in postmenopausal women. However, The Women's Health Initiative (WHI) study has found that women receiving estrogen plus progestin had a significantly higher risk of breast cancer, coronary heart disease, stroke, and pulmonary embolus. In the present study, we examined whether estrogen prevents mechanisms that relate to plaque formation by inhibiting monocyte adhesion to endothelial cells. ECV304 cells, an endothelial cell line that normally expresses minimal estrogen receptor (ER)α, were transfected with an ERα expression plasmid. Treatment with tumor necrosis factor (TNF)-α increased expression of vascular cell adhesion molecule (VCAM)-1 mRNA, activation of nuclear factor-κB (NF-κB), and U937 cell adhesion in ECV304 cells. These effects of TNF-α were not significantly inhibited by pretreatment of native ECV304 cells with 17β-estradiol (E 2 ). In ECV304 cells overexpressing ERα, E 2 significantly inhibited the effects of TNF-α on NF-κB activation, VCAM-1 expression, and U937 cell adhesion. These findings suggest E 2 suppresses inflammatory cell adhesion to vascular endothelial cells that possess functional estrogen receptors. The mechanism of suppression may involve inhibition of NF-κB-mediated up-regulation of VCAM-1 expression induced by atherogenic stimuli. E 2 may prevent plaque formation, as first stage of atheroscrelosis through inhibiting adhesion monocytes to endothelial cell. Actions of estrogen replacement therapy can be assessed in terms of densities of functional ERα.