Ggps1 deficiency in the uterus results in dystocia by disrupting uterine contraction.
Ggps1 deficiency in the uterus results in dystocia by disrupting uterine contraction.
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子宫中的 Ggps1 缺陷会扰乱子宫收缩而导致难产
DOI：
10.1093/jmcb/mjaa066
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发表时间：
2021-05-07
影响因子：
5.5
通讯作者：
Li CJ
中科院分区：
文献类型：
--
作者：
Sang YJ;Wang Q;Zheng F;Hua Y;Wang XY;Zhang JZ;Li K;Wang HQ;Zhao Y;Zhu MS;Sun HX;Li CJ
难产是一个严重的问题，孕妇，它增加了剖宫产率。虽然子宫功能障碍的病因不明，但它是剖宫产和临床难产的原因，导致新生儿发病率和死亡率;因此，迫切需要新的治疗药物。以往的研究表明，他汀类药物，抑制甲羟戊酸（MVA）途径的胆固醇合成，可以降低早产的发生率，但他汀类药物对孕妇的安全性尚未得到充分的评价。因此，为了明确地检查MVA途径在妊娠和分娩中的功能，我们采用了一种遗传方法，通过使用子宫肌层细胞特异性缺失的香叶基香叶基焦磷酸合酶（Ggps 1）小鼠。我们发现子宫肌层细胞中Ggps 1的缺乏导致子宫收缩受损，导致胚胎着床中断和难产。对潜在机制的研究表明，Ggps 1是子宫收缩所必需的，通过调节RhoA异戊烯化以激活RhoA/Rock 2/p-MLC途径来确保成功分娩。我们的工作表明，干扰MVA途径可能会导致怀孕女性分娩过程中的问题，但用补充的焦磷酸法呢酯或焦磷酸香叶基香叶基酯修饰蛋白质异戊二烯化可能是避免副作用的策略。
Dystocia is a serious problem for pregnant women, and it increases the cesarean section rate. Although uterine dysfunction has an unknown etiology, it is responsible for cesarean delivery and clinical dystocia, resulting in neonatal morbidity and mortality; thus, there is an urgent need for novel therapeutic agents. Previous studies indicated that statins, which inhibit the mevalonate (MVA) pathway of cholesterol synthesis, can reduce the incidence of preterm birth, but the safety of statins for pregnant women has not been thoroughly evaluated. Therefore, to unambiguously examine the function of the MVA pathway in pregnancy and delivery, we employed a genetic approach by using myometrial cell-specific deletion of geranylgeranyl pyrophosphate synthase (Ggps1) mice. We found that Ggps1 deficiency in myometrial cells caused impaired uterine contractions, resulting in disrupted embryonic placing and dystocia. Studies of the underlying mechanism suggested that Ggps1 is required for uterine contractions to ensure successful parturition by regulating RhoA prenylation to activate the RhoA/Rock2/p-MLC pathway. Our work indicates that perturbing the MVA pathway might result in problems during delivery for pregnant females, but modifying protein prenylation with supplementary farnesyl pyrophosphate or geranylgeranyl pyrophosphate might be a strategy to avoid side effects.
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