17 -Estradiol Up-Regulates Vascular Endothelial Growth Factor Receptor-2 Expression in Human Myometrial Microvascular Endothelial Cells: Role of Estrogen Receptor- and -

Estrogen has a cardiovascular protective role in women due in part to its effect on the vasculature. The roles of the two estrogen receptors (ERs), ER and ER , in the vascular actions of estrogen are unclear, as are effects of estrogen on microvascular endothelial cells (MEC) derived from sex steroid-responsive tissues. The present study demonstrates that 17 -estradiol, but not progesterone, increases vascular endothelial growth factor (VEGF) receptor (VEGFR) expression on human myometrial MEC measured using biotin-recombinant human (rh) VEGF165 and flow cytometry. This response occurred in a timeand dose-dependent manner, with significantly increased rhVEGF165 binding at 3 h and maximal responses between 0.1 and 10 nmol/liter 17 -estradiol, which was blocked by the antiestrogen ICI 182,780. Approximately 60% of samples demonstrated this response to 17 -estradiol. All samples of myometrial MEC expressed both ER mRNA and protein demonstrated by semiquantitative RT-PCR and Western blotting. However, ER mRNA and protein were expressed in only 13 of 21 MEC samples. There was a significant association between ER expression in myometrial MEC and their ability to respond to 17 -estradiol by increasing rhVEGF165 binding. 17 -estradiol increased VEGFR-2 expression in ER -expressing MEC isolates, which also demonstrated increased rhVEGF165 binding, but failed to have these effects on ER negative samples. Similarly, 17 -estradiol augmented VEGF-induced MEC proliferation in ER -expressing MEC samples, which was blocked by ICI 182,780. These observations suggest that 17 -estradiol increases VEGFR-2 expression on human myometrial MEC promoting endothelial cell proliferation, an effect that varies between subjects and appears to be mediated primarily by ER . (J Clin Endocrinol Metab 87: 4341–4349, 2002)