Loss of cannabinoid receptor CB1 induces preterm birth.
Loss of cannabinoid receptor CB1 induces preterm birth.
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DOI：
10.1371/journal.pone.0003320
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发表时间：
2008-10-03
期刊：
影响因子：
3.7
通讯作者：
Dey SK
中科院分区：
文献类型：
--
作者：
Wang H;Xie H;Dey SK
早产约占妇女怀孕的10%，是一个巨大的社会、临床和经济负担。然而，其根本原因在很大程度上仍然不明。新出现的证据表明，通过大麻素受体CB 1的内源性大麻素信号在动物和人类的多次早孕事件中起着关键作用。由于我们以前的研究表明，CB 1的损失推迟了正常的植入窗口在小鼠中，我们推测，CB 1的缺陷会影响分娩事件。利用分别编码CB 1、CB 2和环氧合酶-1的Cnr 1、Cnr 2和Ptgs 1靶向缺失的小鼠模型，我们研究了CB 1或CB 2沉默对分娩发作的后果。我们观察到，遗传或药理学失活的CB 1，而不是CB 2，诱导早产的小鼠。卵巢类固醇激素的循环水平的放射免疫分析表明，CB 1失活导致的早产与分娩前孕酮/雌激素比值的改变相关。更引人注目的是，通过将CB 1缺陷引入Ptgs 1缺失小鼠，可以纠正Ptgs 1缺失小鼠妊娠时间延长和分娩失败的表型缺陷。此外，CB 1的损失导致异常分泌的促肾上腺皮质激素释放激素和皮质酮在妊娠后期。在没有CB 1的情况下，这种改变的促肾上腺皮质激素释放激素驱动的内分泌活动的病理生理学意义是显而易见的，从我们随后的研究结果，选择性促肾上腺皮质激素释放激素拮抗剂能够恢复正常的分娩时间在Cnr 1缺陷小鼠。相反，野生型女性接受过量的皮质酮诱导早产。CB 1缺乏改变正常的孕酮和雌激素水平诱导小鼠早产。这种缺陷与环氧合酶-1产生的洋地黄素无关。此外，CB 1失活导致异常的促肾上腺皮质激素释放激素和皮质酮活动之前分娩，这表明CB 1调节劳动与促肾上腺皮质激素释放激素驱动的内分泌轴相互作用。
Preterm birth accounting approximate 10% of pregnancies in women is a tremendous social, clinical and economic burden. However, its underlying causes remain largely unknown. Emerging evidence suggests that endocannabinoid signaling via cannabinoid receptor CB1 play critical roles in multiple early pregnancy events in both animals and humans. Since our previous studies demonstrated that loss of CB1 defers the normal implantation window in mice, we surmised that CB1 deficiency would influence parturition events. Exploiting mouse models with targeted deletion of Cnr1, Cnr2 and Ptgs1 encoding CB1, CB2 and cyclooxygenase-1, respectively, we examined consequences of CB1 or CB2 silencing on the onset of parturition. We observed that genetic or pharmacological inactivation of CB1, but not CB2, induced preterm labor in mice. Radioimmunoassay analysis of circulating levels of ovarian steroid hormones revealed that premature birth resulting from CB1 inactivation is correlated with altered progesterone/estrogen ratios prior to parturition. More strikingly, the phenotypic defects of prolonged pregnancy length and parturition failure in mice missing Ptgs1 were corrected by introducing CB1 deficiency into Ptgs1 null mice. In addition, loss of CB1 resulted in aberrant secretions of corticotrophin-releasing hormone and corticosterone during late gestation. The pathophysiological significance of this altered corticotrophin-releasing hormone-driven endocrine activity in the absence of CB1 was evident from our subsequent findings that a selective corticotrophin-releasing hormone antagonist was able to restore the normal parturition timing in Cnr1 deficient mice. In contrast, wild-type females receiving excessive levels of corticosterone induced preterm birth. CB1 deficiency altering normal progesterone and estrogen levels induces preterm birth in mice. This defect is independent of prostaglandins produced by cyclooxygenase-1. Moreover, CB1 inactivation resulted in aberrant corticotrophin-releasing hormone and corticosterone activities prior to parturition, suggesting that CB1 regulates labor by interacting with the corticotrophin-releasing hormone-driven endocrine axis.
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