OPPOSING ACTIONS OF PROSTAGLANDINS AND OXYTOCIN DETERMINE THE ONSET OF MURINE LABOR

Prostaglandins (PGs) have been recently proven essential for parturiti on in mice. To dissect the contributions of the two cyclooxygenase (CO X) isoforms to the synthesis of PGs during pregnancy, we have characte rized the parturition phenotype of COX-l-deficient mice. We find that mice with targeted disruption of the COX-1 gene have delayed parturiti on resulting in neonatal death. Results of matings of COX-l-deficient females with COX-1 intact males, and blastocyst transfer of COX-l-defi cient or -intact embryos into wild-type foster mothers, proved necessi ty and sufficiency of maternal COX-1 for the normal onset of labor. CO X-1 expression is induced in gravid murine uterus and by in situ hybri dization; this induction is localized to the decidua. Measurement of u terine PGs further confirmed that COX-1 accounted for the majority of PGF2 alpha production. To evaluate the interaction of PGs with oxytoci n during murine labor, we generated mice deficient in both oxytocin an d COX-I, Surprisingly, the combined oxytocin and COX-l-deficient mice initiated labor at the normal time. COX-l-deficient mice demonstrated impaired luteolysis, as evidenced by elevated serum progesterone conce ntration and ovarian histology late in gestation, and delayed inductio n of uterine oxytocin receptors, In contrast, simultaneous oxytocin an d COX-1 deficiency restored the normal onset of labor by allowing lute olysis in the absence of elevated PGF2 alpha production, These finding s demonstrate that COX-1 is essential for normal labor in the mouse, w ith a critical function being to overcome the luteotrophic action of o xytocin in late gestation.