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

Centre for Women’s Health Research (C.E.G., M.Z., K.B., P.A.W.R.), Monash University Department of Obstetrics and Gynaecology, Monash Medical Centre, Clayton, Victoria 3168, Australia; and Prince Henry’s Institute of Medical Research (S.C., P.J.F.), Clayton, Victoria 3168, Australia

Address all correspondence and requests for reprints to: Dr. Caroline Gargett, Centre for Women’s Health Research, Monash University Department of Obstetrics and Gynaecology, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia. E-mail: . caroline.gargett{at}med.monash.edu.au

Abstract

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 ERß, 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 17ß-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 time- and dose-dependent manner, with significantly increased rhVEGF₁₆₅ binding at 3 h and maximal responses between 0.1 and 10 nmol/liter 17ß-estradiol, which was blocked by the antiestrogen ICI 182,780. Approximately 60% of samples demonstrated this response to 17ß-estradiol. All samples of myometrial MEC expressed both ERß 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 17ß-estradiol by increasing rhVEGF₁₆₅ binding. 17ß-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, 17ß-estradiol augmented VEGF-induced MEC proliferation in ER-expressing MEC samples, which was blocked by ICI 182,780. These observations suggest that 17ß-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.

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