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Multiple Roles for Heparin-Binding Epidermal Growth Factor-Like Growth Factor Are Suggested by Its Cell-Specific Expression during the Human Endometrial Cycle and Early Placentation¹

Department of Obstetrics and Gynecology, C. S. Mott Center for Human Growth and Development (R.E.L., R.K., R.R., D.R.A.), and Departments of Pathology (N.D.R.) and Anatomy and Cell Biology (D.R.A.), Wayne State University, Detroit, Michigan 48201-1415; and the Departments of Obstetrics and Gynecology and Molecular and Integrative Physiology, Ralph L. Smith Research Center, University of Kansas Medical Center (S.K.De., J.W., S.K.Da.), Kansas City, Kansas 66160-7336

Address all correspondence and requests for reprints to: Dr. D. R. Armant, Department of Obstetrics and Gynecology, C. S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, 275 East Hancock Avenue, Detroit, Michigan 48201-1415. E-mail: d.armant{at}wayne.edu

Embryonic expression of the epidermal growth factor (EGF) receptor as well as embryonic and steroid-dependent uterine secretion of its ligand, heparin-binding EGF-like growth factor (HB-EGF), are temporally associated with the period of blastocyst implantation. We examined the temporal cell type-specific expression of HB-EGF in human endometrium during the menstrual cycle by immunohistochemistry and in situ hybridization. Early first trimester implantation sites were also examined to determine HB-EGF protein levels in decidual and fetal tissues. In the endometrial stroma, HB-EGF protein expression increased markedly during the late proliferative phase and then decreased in the early secretory phase. By contrast, luminal and glandular epithelial cells as well as blood vessel endothelium accumulated the protein between midcycle and cycle day 20, with peak expression observed during the period of uterine receptivity for implantation. HB-EGF expression decreased dramatically at the end of the cycle, before menses. Spatiotemporal expression of HB-EGF messenger ribonucleic acid demonstrated a similar pattern. During early pregnancy, HB-EGF immunostaining was noted in the decidua and in both villous and extravillous trophoblast populations. These findings suggest that HB-EGF promotes implantation and trophoblast invasion through paracrine and autocrine signaling as cells penetrate the stroma and displace the arteriole endothelium.

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