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 placentation

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 th e period of blastocyst implantation. We examined the temporal cell type-spe cific expression of I-IB-EGF in human endometrium during the menstrual cycl e 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 expr ession increased markedly during the late proliferative phase and then decr eased in the early secretory phase. By contrast, luminal and glandular epit helial cells as well as blood vessel endothelium accumulated the protein be tween midcycle and cycle day 20, with peak expression observed during the p eriod of uterine receptivity for implantation. HB-EGF expression decreased dramatically at the end df the cycle, before menses. Spatiotemporal express ion of HB-EGF messenger ribonucleic acid demonstrated a similar pattern. Du ring early pregnancy, HB-EGF immunostaining was noted in the decidua and in both villous and extravillous trophoblast populations. These findings sugg est that HB-EGF promotes implantation and trophoblast invasion through para crine and autocrine signaling as cells penetrate the stroma and displace th e arteriole endothelium.