Progesterone regulation of heparin-binding epidermal growth factor-like growth factor gene expression during sensitization and decidualization in the rat uterus: effects of the antiprogestin, ZK 98.299

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The ability of uterine stromal cells to respond to embryo attachment or an artificial decidual stimulus and the development and maintenance of decidual cells are primarily regulated by progesterone (P), yet few P-induced genes have been described. Previously, we reported that P stimulated the expression of heparin-binding epidermal growth factor-like growth factor (HB-EGF) messenger RNA (mRNA) in rat uterine stromal cells. We now present evidence that the effects of P on HB-EGF expression are blocked by treatment with ZK98299 (onapristone), indicating that they are receptor mediated. Additionally, animals treated with ZK98299 alone or together with P failed to respond to a decidual stimulus, suggesting that stromal cell sensitivity was inhibited. These results provide further evidence that HB-EGF plays a role in the development of stromal cell sensitivity to decidual stimuli. Expression of HB-EGF mRNA was also investigated in differentiating stromal cells after an artificial decidual stimulus. HB-EGF mRNA levels increased from 8-48 h after stimulation, the same interval in which stromal cells exhibit maximal mitotic activity. In situ hybridization revealed that stromal and decidual cells were the major sources of HB-EGF mRNA during this period. These results suggest that HB-EGF acts as an autocrine/paracrine factor in stimulating stromal cell proliferation after the induction of decidualization.