Prostacyclin primes pregnant human myometrium for an enhanced contractile response in parturition.
Prostacyclin primes pregnant human myometrium for an enhanced contractile response in parturition.
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DOI：
10.1172/jci33800
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发表时间：
2008-12-01
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影响因子：
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通讯作者：
Martin, Kathleen A
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作者：
Fetalvero, Kristina M;Zhang, Peisheng;Martin, Kathleen A
对分娩过程中调节子宫肌层从静止妊娠状态向活跃收缩状态转变的分子事件的不完全理解阻碍了早产改进疗法的发展。在子宫肌层激活期间，使平滑肌收缩的蛋白质被上调，允许对收缩激动剂的最大反应性，从而产生强的阶段性收缩。一种这样的蛋白质考克斯-2的上调产生诱导收缩的PG。有趣的是，临产前子宫肌层产生的主要PG是前列环素（PGI 2），一种平滑肌松弛剂。然而，在这里，我们已经表明，PGI 2受体（IP）的激活上调表达的几个收缩蛋白和差距连接蛋白连接蛋白43通过cAMP/PKA信号在人子宫肌层组织中的器官和细胞培养。在功能上，这些IP依赖的基因表达的变化促进了增强收缩反应，催产素在怀孕的人子宫肌层组织条，这是抑制IP拮抗剂RO 3244794。此外，收缩蛋白诱导依赖于暴露于PGI 2类似物伊洛前列素的浓度和时间，并被RO 3244794和PKA敲低阻断。因此，我们认为PGI 2介导的收缩蛋白和连接蛋白43的上调是子宫肌层激活的关键步骤，允许最大的收缩反应。我们的观察结果对分娩前子宫肌层的激活有重要意义。
An incomplete understanding of the molecular events that regulate the myometrial transition from the quiescent pregnant state to the active contractile state during labor has hindered the development of improved therapies for preterm labor. During myometrial activation, proteins that prime the smooth muscle for contraction are upregulated, allowing maximal responsiveness to contractile agonists and thereby producing strong phasic contractions. Upregulation of one such protein, COX-2, generates PGs that induce contractions. Intriguingly, the predominant myometrial PG produced just prior to labor is prostacyclin (PGI2), a smooth muscle relaxant. However, here we have shown that activation of PGI2 receptor (IP) upregulated the expression of several contractile proteins and the gap junction protein connexin 43 through cAMP/PKA signaling in human myometrial tissue in organ and cell culture. Functionally, these IP-dependent changes in gene expression promoted an enhanced contractile response to oxytocin in pregnant human myometrial tissue strips, which was inhibited by the IP antagonist RO3244794. Furthermore, contractile protein induction was dependent on the concentration and time of exposure to the PGI2 analog iloprost and was blocked by both RO3244794 and PKA knockdown. We therefore propose that PGI2-mediated upregulation of contractile proteins and connexin 43 is a critical step in myometrial activation, allowing for a maximal contractile response. Our observations have important implications regarding activation of the myometrium prior to the onset of labor.