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

The ability of uterine stromal cells to respond to embryo attachment o r 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 s timulated the expression of heparin-binding epidermal growth factor li ke growth factor (HB-EGF) messenger RNA (mRNA) in rat uterine stromal cells. We now present evidence that the effects of P on HB-EGF express ion are blocked by treatment with ZK98299 (onapristone), indicating th at they are receptor mediated. Additionally, animals treated with ZK98 299 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 a rtificial decidual stimulus. HB-EGF mRNA levels increased from 8-48 h after stimulation, the same interval in which stromal cells exhibit ma ximal mitotic activity. In situ hybridization revealed that stromal an d decidual cells were the major sources of HB-EGF mRNA during this per iod. These results suggest that HB-EGF acts as an autocrine/paracrine factor in stimulating stromal cell proliferation after the induction o f decidualization.