Prostaglandin-Endoperoxide Synthase 1 Mediates the Timing of Parturition in Mice Despite Unhindered Uterine Contractility
Prostaglandin-Endoperoxide Synthase 1 Mediates the Timing of Parturition in Mice Despite Unhindered Uterine Contractility
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DOI：
10.1210/en.2017-00647
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发表时间：
2018-01-01
期刊：
影响因子：
4.8
通讯作者：
Reese, Jeff
中科院分区：
文献类型：
--
作者：
Herington, Jennifer L.;O'Brien, Christine;Reese, Jeff
环氧合酶（考克斯）衍生的洋地黄素刺激子宫收缩并使宫颈为分娩做好准备。先前的报道表明考克斯-1基因敲除（KO）小鼠由于黄体溶解受损而表现出延迟分娩，但迟发性分娩的机制仍不清楚。在这里，我们检查了正常分娩的关键因素，以确定是否有任何可以解释延迟分娩表型。妊娠的考克斯-1基因敲除小鼠没有显示出胚胎植入或植入后生长时间的改变。尽管收缩相关蛋白（CAP）的信使RNA在考克斯-1 KO和野生型（WT）子宫肌层之间表达差异，但CAP激动剂诱导的细胞内钙释放、自发或催产素（OT）诱导的离体子宫收缩力或体内子宫收缩压均无差异。考克斯-1 KO小鼠的延迟分娩持续存在，尽管外源性OT治疗。通过卵巢切除术或给予P-4拮抗剂RU 486，使孕激素（P-4）戒断减少了考克斯-1 KO小鼠的延迟分娩表型。由于产前P-4水平在考克斯-1 KO雌性中不下降，因此检查了P-4处理的WT小鼠的这种激素对体内子宫收缩力和离体宫颈扩张的影响。P-4处理的WT小鼠分娩延迟，但子宫收缩力正常。在预期分娩当天，考克斯-1 KO小鼠的颈部扩张性降低，在长期P-4治疗的WT小鼠中也降低。总的来说，这些发现表明，尽管存在强烈的子宫收缩，但考克斯-1 KO小鼠的延迟分娩是黄体溶解和宫颈扩张受损的结果。
Cyclooxygenase (COX)-derived prostaglandins stimulate uterine contractions and prepare the cervix for parturition. Prior reports suggest Cox-1 knockout (KO) mice exhibit delayed parturition due to impaired luteolysis, yet the mechanism for late-onset delivery remains unclear. Here, we examined key factors for normal onset of parturition to determine whether any could account for the delayed parturition phenotype. Pregnant Cox-1KO mice did not display altered timing of embryo implantation or postimplantation growth. Although messenger RNAs of contraction-associated proteins (CAPs) were differentially expressed between Cox-1KO and wild-type (WT) myometrium, there were no differences in CAP agonist-induced intracellular calcium release, spontaneous or oxytocin (OT)-induced ex vivo uterine contractility, or in vivo uterine contractile pressure. Delayed parturition in Cox-1KO mice persisted despite exogenous OT treatment. Progesterone (P-4) withdrawal, by ovariectomy or administration of the P-4-antagonist RU486, diminished the delayed parturition phenotype of Cox-1KO mice. Because antepartum P-4 levels do not decline in Cox-1KO females, P-4-treated WT mice were examined for the effect of this hormone on in vivo uterine contractility and ex vivo cervical dilation. P-4-treated WT mice had delayed parturition but normal uterine contractility. Cervical distensibility was decreased in Cox-1KO mice on the day of expected delivery and reduced in WT mice with long-term P-4 treatment. Collectively, these findings show that delayed parturition in Cox-1KO mice is the result of impaired luteolysis and cervical dilation, despite the presence of strong uterine contractions.