Cell death by apoptosis takes place during the growth and development of vertebrate tissues and during the adult function of tissues. As a complement to mitosis, apoptosis has a vital function in the uterus in maintaining the homeostasis of cell number during the estrous cycle and in the tissue remodeling inherent in blastocyst implantation and development of the placenta. The proposed research will examine the pattern of expression and hormonal control of apoptosis in endometrial epithelial and stromal cells during blastocyst implantation and during decidualization. Our hypothesis is that progesterone and estrogen secretion during early pregnancy controls not only the growth and differentiation of endometrial cells but also controls their regression by apoptosis through the control of the synthesis of TGF-beta's and/or their receptors. To examine this hypothesis, the following specific aims are proposed: (l) We will determine the control of apoptosis by progesterone and estrogen and establish the kinetics of this cellular process in luminal epithelial cells in response to a deciduogenic stimulus and in stroma cells during decidualization in hormone-treated ovariectomized rats, pseudopregnant rats, and pregnant rats. Antiprogestins will be used in these studies to examine progesterone control of endometrial transformation following implantation. (2) We will determine the growth factor control of stromal cell apoptosis focusing upon TGF-beta2 as the growth factor which controls stromal apoptosis during decidual regression by a paracrine and/or autocrine mechanism. The synthesis of TGF-beta's the specific cells will be examined by immunohistochemistry and in situ hybridization. We will measure receptor levels for TGF-beta's and characterize the receptor proteins. (3) The biochemical mechanisms by which TGF-beta initiates apoptosis in endometrial stromal cells will be examined. We will measure the response to TGF-beta of specific genes which have been identified as early participants in the initiation of apoptosis. The role of these genes in stromal apoptosis will be determined by inhibiting their expression with antisense oligodeoxynucleotides corresponding to translation start regions. The hypothesis that an influx of Ca++ is required for apoptosis will be tested by examining the effect of TGF-beta on intracellular levels of Ca++ of cultured stromal cells and by determining effects of blocking Ca++ influx on apoptosis. Completion of these studies should contribute to our understanding of fundamental cellular and biochemical mechanisms of blastocyst implantation and decidualization.
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