Metabolic mechanisms of uterine contractility in labor

项目摘要/摘要 产妇肥胖与较低的自然分娩率、较慢的宫颈扩张进程、 并增加了分娩停止障碍和诱导失败的风险。此外，与苗条的女性相比， 肥胖妇女的剖腹产率几乎高出三倍，使她们面临更大的风险。 孕产妇和新生儿发病率。而母亲肥胖和异常分娩之间的联系 尽管已经有了很好的记录，但造成这种情况的机制仍不清楚。有证据表明 肥胖会导致女性子宫收缩功能障碍。女性子宫平滑肌(肌层) 肥胖者收缩的力量和频率比正常体重的女性子宫肌层和 肥胖女性需要更高剂量的催产素来实现阴道分娩，这表明这是不正常的 收缩反应。我们开发了一种饮食诱导肥胖的小鼠模型，该模型概括了 在肥胖女性中可以看到功能失调的劳动模式，可以应用于进一步的机械学研究。 在这里，我们的目标是提供一个控制子宫肌层能量代谢的机械性理解。 以及分娩期间的肥胖小鼠。我们关注能量新陈代谢是因为 在分娩过程中，宫颈扩张和胎儿排出--在人类持续数小时到数天--会产生很高的 子宫肌层的能量需求。我们的初步数据还表明，肥胖的大坝显著地 脂肪(甘油三酯和脂肪酸)含量较高，导致脂肪酸的基因表达增加 摄取和储存、糖酵解通量异常和关键葡萄糖转运体表达减少 子宫肌层在足月时明显高于对照组。因此，我们的总体假设是过量的脂肪酸和 肥胖大鼠子宫肌层中的甘油三酯抑制葡萄糖氧化，而葡萄糖氧化是启动和 早产的进展。尽管每年有数以百万计的妇女接生，但我们知道 令人惊讶的是，关于子宫肌层如何满足健康女性或患有糖尿病的女性的能量需求 肥胖。这个项目的目标是(1)确定饮食诱导的肥胖对自发性和 激动剂诱导的小鼠子宫肌层收缩和分娩以及(2)确定肌层的作用 能量底物利用率对小鼠分娩期间子宫收缩的影响。我们提议的研究将 提供必要的机制数据，以开发药物和行为干预措施，以优化 分娩过程中肌层能量的储存和利用。最终，这项研究可能会让我们改进 数百万肥胖妇女的产科结局。

PROJECT SUMMARY/ABSTRACT Maternal obesity is associated with lower rates of spontaneous labor, slower progress of cervical dilation, and increased risks of labor arrest disorders and induction failure. Additionally, compared to lean women, women with obesity have a nearly three-fold higher rate of cesarean delivery, putting them at increased risk of maternal and neonatal morbidity. While the association between maternal obesity and abnormal labor has been well documented, the mechanisms responsible for this remain unknown. Evidence suggests that obesity causes uterine contractility dysfunction in women. Uterine smooth muscle (myometrium) from women with obesity contracts with less force and frequency than myometrium from normal-weight women and women with obesity require higher doses of oxytocin to achieve a vaginal delivery, suggesting abnormal contractile response. We developed a mouse model of diet-induced obesity that recapitulates the dysfunctional labor patterns seen in women with obesity and can be applied for further mechanistic studies. Here, our objective is to provide a mechanistic understanding of myometrial energy metabolism in control and obese mice during parturition. We focus on energy metabolism because the contractility required for cervical dilation and expulsion of the fetus during labor – lasting for hours to days in humans – places a high energy demand on the myometrium. Our preliminary data also suggest that obese dams have significantly higher lipid (triglyceride and fatty acids) content, increased expression of genes responsible for fatty acid uptake and storage, dysfunctional glycolytic flux, and decreased expression of a key glucose transporter in the myometrium than control dams at term. Thus, our overall hypothesis is that excess fatty acid and triglycerides in the myometrium of obese dams inhibit glucose oxidation, which is required for initiation and progression of early labor. Despite the fact that millions of women deliver an infant each year, we know surprisingly little about how the myometrium meets its energy demands in healthy women or those with obesity. The goals of this project are to (1) define the effects of diet-induced obesity on spontaneous and agonist-induced myometrial contractility and parturition in mice and (2) determine the effects of myometrial energy substrate availability on uterine contractility during labor in the mouse. Our proposed research will provide the necessary mechanistic data to develop pharmacologic and behavioral interventions to optimize myometrial energy storage and utilization during labor. Ultimately, this research may allow us to improve obstetric outcomes for millions of women with obesity.