Endocrine Abstracts

Cyclooxygenase (COX), the rate-limiting enzyme in prostaglandin (PG) biosynthesis exists in two isoforms, COX-1 and COX-2. They are encoded by two separate genes, and show cell-type specific expression and regulation. The expression of COX-1 is constitutive, whereas that of COX-2 is inducible by cytokines/growth factors or inflammatory stimuli. Since the processes of ovulation and implantation are considered analogous to 'proinflammatory' responses, and the involvement of PGs in these processes has long been speculated. We have shown that COX-2, but not COX-1, is expressed in an implantation-specific manner in the mouse uterus. We have also shown recently that the targeted disruption of the COX-2, but not the COX-1, gene in the mouse produces failures in ovulation, fertilization, implantation and decidualization. There is now evidence that other species including a sub-human primate, baboon, exhibit implantation-specific COX-2 expression during early pregnancy. These findings suggest that COX-2 derived PGs are important during early pregnancy in various species. Prostacyclin (PGI2) is the major COX-2 derived PG at the implantation site and implantation defects in COX-2 mutant mice are considerably rescued by carbaprostacylin (cPGI), a more stable analogue of PGI2. This effect of PGI2 appears to mediated via activation of PPARd, a member of the steroid hormone nuclear receptor superfamily. However, the mechanism(s) by which activation of PPARd mediates the implantation process is not clearly understood. We have now evidence to suggest that COX-2 derived PGs are involved in uterine vascular permeability and angiogenesis required for implantation. This work is funded by NIH and Mellon Foundation.