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Heparin-Binding Epidermal Growth Factor and Its Receptors Mediate Decidualization and Potentiate Survival of Human Endometrial Stromal Cells

Nuffield Department of Obstetrics and Gynaecology (K.C., N.K., J.C., S.M., D.H.B., H.J.M.), University of Oxford, Women’s Centre, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom; and Research School of Biosciences (W.J.G.), University of Kent, Canterbury CT2 7NJ, United Kingdom

Address all correspondence and requests for reprints to: Helen J. Mardon, Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Women’s Centre, Level 3, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom. E-mail: helen.mardon{at}obs-gyn.ox.ac.uk.

Heparin-binding epidermal growth factor (HB-EGF) has pleiotropic biological functions in many tissues, including those of the female reproductive tract. It facilitates embryo development and mediates implantation and is thought to have a function in endometrial receptivity and maturation. The mature HB-EGF molecule manifests its activity as either a soluble factor (sol-HB-EGF) or a transmembrane precursor (tm-HB-EGF) and can bind two receptors, EGFR and ErbB4/HER4. In this study, we identify factors that modulate expression of HB-EGF, EGFR, and ErbB4 in endometrial stromal cells in vitro. We demonstrate that levels of sol- and tm-HB-EGF, EGFR, and ErbB4 are increased by cAMP, a potent inducer of decidualization of the endometrial stroma. We also show that production of sol- and tm-HB-EGF is differentially modulated by TNF and TGFß. Our data suggest that HB-EGF has a function in endometrial maturation in mediating decidualization and attenuating TNF- and TGFß-induced apoptosis of endometrial stromal cells.

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