Uterine secretion of prostaglandin (PG)F2alpha in nonprimates and, probably, ovarian production in primates is the proximate cause of regression of the corpus luteum (CL). Uterine PGF2alpha secretion is involved in the process of menstruation and appears to be a critical component for the initiation of labor in several species. This project is directed towards defining the cellular, receptor, and molecular mechanisms involved in the pulsatile release of prostaglandin (PG) F2alpha during luteolysis and its abrogation in early pregnancy using both in vivo and in vitro techniques. The broad, long term objectives are to further our understanding of basic mechanisms regulating the evolution of endometrial receptors for oxytocin (OT) and, hence, the regulation of uterine synthesis of PGF2alpha. In the past few years the discovery of OT in the CL of the ovine, bovine, and primate species has provided new insights into the regulation of pulsatile PGF2alpha secretion. Because of the existence of unique surgical models in the sheep, this species is the animal of choice to investigate these complex systems. We have developed an integrated hypothesis to explain the pulsatile release of PGF2alpha during luteolysis and its abrogation during early pregnancy, centering on the evolution of OT receptors (rOT) in the endometrium and the regulation of OT secretion by the CL. We have recently shown that the gene for OT is fully expressed in the ovine CL and now have obtained its full sequence. Preliminary evidence indicates that OT and OT-mRNA may be processed differently in the early pregnant and hysterectomized animal, as opposed to the cyclic animal, since there is an unexplained loss of OT from the CL in early pregnancy and after hysterectomy. We will determine if this loss of OT from CL is due to secretion, crinophagy or a combination of both. We will also examine the desensitization mechanism which we have recently discovered for PGF2alpha- stimulated release of luteal OT. This desensitization mechanism in the CL appears to dictate certain components of the pulsatile system of PGF2alpha release from the uterus which may, in turn, be controlled by the availability of uterine rOT. The evolution of the latter will also be examined by direct measurement and by the detection of mRNA for rOT using the Xenopus oocyte system. Using a combination of unique physiological animal models, receptor measurement, microscopic localization and molecular approaches, we will dissect the underlying mechanisms which regulate the pulsatile secretion of PGF2alpha. The knowledge of the mechanisms of hormone secretion and receptor desensitization obtained by this study will be relevant to the general phenomenon of the pulsatile secretion of hormones observed in many species including the human. Moreover, our proposed studies on the evolution and molecular biology of the OT receptor is highly relevant to the onset of labor since recent findings indicate a pivotal role for the OT receptor in this process. Such information may provide new insights into the etiology of premature labor in women, a leading cause of infant mortality.
