Gross G A, Imamura T, Luedke C, Vogt S K, Olson L M, Nelson D M, Sadovsky Y, Muglia L J
Department of Obstetrics and Gynecology, Washington University School of Medicine, One Children's Place, St. Louis, MO 63110, USA.
Proc Natl Acad Sci U S A. 1998 Sep 29;95(20):11875-9. doi: 10.1073/pnas.95.20.11875.
Prostaglandins (PGs) have been recently proven essential for parturition in mice. To dissect the contributions of the two cyclooxygenase (COX) isoforms to the synthesis of PGs during pregnancy, we have characterized the parturition phenotype of COX-1-deficient mice. We find that mice with targeted disruption of the COX-1 gene have delayed parturition resulting in neonatal death. Results of matings of COX-1-deficient females with COX-1 intact males, and blastocyst transfer of COX-1-deficient or -intact embryos into wild-type foster mothers, proved necessity and sufficiency of maternal COX-1 for the normal onset of labor. COX-1 expression is induced in gravid murine uterus and by in situ hybridization; this induction is localized to the decidua. Measurement of uterine PGs further confirmed that COX-1 accounted for the majority of PGF2alpha production. To evaluate the interaction of PGs with oxytocin during murine labor, we generated mice deficient in both oxytocin and COX-1. Surprisingly, the combined oxytocin and COX-1-deficient mice initiated labor at the normal time. COX-1-deficient mice demonstrated impaired luteolysis, as evidenced by elevated serum progesterone concentration and ovarian histology late in gestation, and delayed induction of uterine oxytocin receptors. In contrast, simultaneous oxytocin and COX-1 deficiency restored the normal onset of labor by allowing luteolysis in the absence of elevated PGF2alpha production. These findings demonstrate that COX-1 is essential for normal labor in the mouse, with a critical function being to overcome the luteotrophic action of oxytocin in late gestation.
前列腺素（PGs）最近已被证明对小鼠分娩至关重要。为了剖析两种环氧化酶（COX）同工型在孕期PGs合成中的作用，我们对COX - 1缺陷小鼠的分娩表型进行了特征分析。我们发现，COX - 1基因靶向破坏的小鼠分娩延迟，导致新生小鼠死亡。COX - 1缺陷雌性与COX - 1完整雄性交配的结果，以及将COX - 1缺陷或完整胚胎移植到野生型代孕母鼠子宫内的结果，证明了母体COX - 1对正常分娩启动的必要性和充分性。通过原位杂交发现，COX - 1在妊娠小鼠子宫中被诱导表达，这种诱导定位于蜕膜。子宫PGs的测量进一步证实，COX - 1占前列腺素F2α（PGF2α）产生的大部分。为了评估小鼠分娩过程中PGs与催产素的相互作用，我们培育了同时缺乏催产素和COX - 1的小鼠。令人惊讶的是，同时缺乏催产素和COX - 1的小鼠在正常时间开始分娩。COX - 1缺陷小鼠表现出黄体溶解受损，这在妊娠后期血清孕酮浓度升高和卵巢组织学检查中得到证实，并且子宫催产素受体的诱导延迟。相比之下，同时缺乏催产素和COX - 1通过在不增加PGF2α产生的情况下允许黄体溶解，恢复了正常的分娩启动。这些发现表明，COX - 1对小鼠正常分娩至关重要，其关键功能是在妊娠后期克服催产素的黄体营养作用。
