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Progestin-Epidermal Growth Factor Regulation of Tissue Factor Expression during Decidualization of Human Endometrial Stromal Cells¹

Department of Obstetrics and Gynecology (C.J.L., G.K., R.R., L.S., F.S.)and Department of Pathology (A.M.), New York University School of Medicine, New York, New York 10016

Address correspondence and requests for reprints to: Charles J. Lockwood, M.D., Professor and Chairman, Department of Obstetrics and Gynecology, New York University School of Medicine, New York, New York 10016.

Perivascular decidualized human endometrial stromal cells (HESCs) are ideally positioned to prevent peri-implantational hemorrhage during endovascular trophoblast invasion by expressing tissue factor (TF), the primary cellular mediator of hemostasis. Earlier in vivo and in vitro studies have demonstrated enhanced TF expression in estradiol (E₂)-primed HESCs during progestin-induced decidualization. However, the absence of estrogen or progesterone response elements from the TF gene promoter suggests that paracrine factor(s) may mediate these effects. We now demonstrate that significant elevation of TF messenger RNA and protein levels in the cultured HESCs require incubation with both epidermal growth factor (EGF) and the progestin medroxyprogesterone acetate (MPA) added, with or without E₂. By contrast, no effects were elicited by adding EGF with E₂, or by the separate additions of EGF, MPA, or E₂ plus MPA. Our finding, that transforming growth factor-alpha, but not transforming growth factor-beta or interleukin 1-beta mimics these EGF effects, indicates that progestin-enhanced TF expression in cultured HESCs requires activation of the EGF receptor (EGFR). Western blot analysis indicated that MPA increased EGFR levels 2- to 3-fold in cultured HESCs. The current results suggest that the progestin up-regulation of TF levels in decidualized HESCs is mediated by enhanced EGFR expression.

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