Opposing actions of prostaglandins and oxytocin determine the onset of murine labor

摘要

Prostaglandins (PGs) have been recently proven essential forparturition in mice. To dissect the contributions of the twocyclooxygenase (COX) isoforms to the synthesis of PGs during pregnancy,we have characterized the parturition phenotype of COX-1-deficientmice. We find that mice with targeted disruption of the COX-1 gene havedelayed parturition resulting in neonatal death. Results of matings ofCOX-1-deficient females with COX-1 intact males, and blastocysttransfer of COX-1-deficient or -intact embryos into wild-type fostermothers, proved necessity and sufficiency of maternal COX-1 for thenormal onset of labor. COX-1 expression is induced in gravid murineuterus and by in situ hybridization; this induction islocalized to the decidua. Measurement of uterine PGs further confirmedthat COX-1 accounted for the majority of PGF2α production. Toevaluate the interaction of PGs with oxytocin during murine labor, wegenerated mice deficient in both oxytocin and COX-1. Surprisingly, thecombined oxytocin and COX-1-deficient mice initiated labor at thenormal time. COX-1-deficient mice demonstrated impaired luteolysis, asevidenced by elevated serum progesterone concentration and ovarianhistology late in gestation, and delayed induction of uterine oxytocinreceptors. In contrast, simultaneous oxytocin and COX-1 deficiencyrestored the normal onset of labor by allowing luteolysis in theabsence of elevated PGF2α production. These findings demonstrate thatCOX-1 is essential for normal labor in the mouse, with a criticalfunction being to overcome the luteotrophic action of oxytocin in lategestation.