Regulation of cell survival in the rat uterus

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Recognition, maintenance and termination of pregnancy are complex processes involving both maternal and embryonic signals. In the rodents during early implantation, endometrial epithelial cells undergo apoptosis. Later, the stromal cells undergo decidualization, which is followed by decidua basalis (DB) regression, involving apoptosis of decidual cells. At the end of pregnancy, a tightly controlled production of prostaglandins is necessary to induce parturition. However, the molecular mechanisms governing endometrial cell apoptosis are not yet defined. Interestingly, our laboratory has showed that individual TGF-b isoforms (TGF-b1, TGF-b2 and TGF-b3) are differently expressed in the uterus during rat pregnancy: TGF-b1 and TGF-b2 are present during implantation and DB regression, whereas TGF-b3 isoform is only present during DB and parturition. We have also provided evidence that distinct TGF-b isoforms can activate distinct signaling pathways in endometrial cells, since only TGF-b3 induces phosphorylation/activation of Akt in endometrial epithelial cells. In the pregnant rat uterus, multiple TGF-b isoforms are often co-expressed: how distinct TGF-b isoform-activated pathways integrate, and shift the balance towards cell survival or cell death in the pregnant uterus, is poorly understood. The overall and long term objective of the proposed research program is to examine and understand the regulation of expression as well as the endocrine, paracrine and autocrine activity of the TGF-b isoforms in the endometrium during the three important phases of pregnancy: 1) implantation, 2) DB regression, and 3) parturition. The short term objectives of the current proposal are to characterize the involvement, the mechanisms of action and interactions of TGF-b isoforms in the (i) regulation of endometrial epithelial cell death at the time of embryo implantation, (ii) stromal cell-induced apoptosis during decidua DB and (iii) prostaglandins regulation and secretion at the time of parturition. Information gained from these studies will help to understand the importance of TGF-b isoforms during these critical reproductive situations and will provide important clues for successful establishment, maintenance and termination of pregnancy.