妊娠期局部子宫收缩力差异:体外缺氧和子宫下垂的作用

Regional uterine contractility differences during pregnancy: The role of hypoxia and ferroptosis in vitro

妊娠期局部子宫收缩力差异:体外缺氧和子宫下垂的作用

Authors: Ruixian Tian, Xuan Li, Jingjing Su, Huihui Yu, Jiajia Fei, Chenyi Xu, Xue Du, Biao Yu, Yunxia Cao, Zongzhi Yin

Source: Life Sciences

PMID: 40185467

DOI: 10.1016/j.lfs.2025.123603

Abstract

Regional variations in uterine contractility during pregnancy have been well-documented. However, the molecular mechanisms underlying these differences remain unclear. To address this, isotonic contraction experiments were conducted on pregnant rat uteri, revealing significantly lower contractility on the placenta-attached side compared to the non-attached side. Interestingly, lactic acid accumulation was higher in the placenta-attached tissue, suggesting metabolic differences between these regions. Muscle contraction requires substantial energy, with adenosine triphosphate (ATP) serving as the direct source of energy, which is predominantly supplied by mitochondria, the cellular energy production centers. Mitochondrial energy generation relies heavily on oxygen availability. To explore the impact of oxygen conditions on uterine smooth muscle cell (USMC) contraction, we cultured these cells under hypoxic conditions. Hypoxia was found to reduce cell contraction and disrupt mitochondrial integrity. Specifically, mitochondria exhibited shrinkage and deformation, characterized by reduced cristae and a collapse of the mitochondrial membrane potential. These structural and functional changes align with hallmarks of ferroptosis. Furthermore, hypoxia stimulated the translocation of dynamic related protein 1 (Drp1) to mitochondria, a process linked to mitochondrial fragmentation. Ferroptosis was downregulated when Drp1 activity was inhibited, highlighting its regulatory role in this process. Collectively, these findings demonstrate that hypoxia induced-ferroptosis impairs mitochondria, leading to reduced energy production and cell viability. This ultimately decreases the contractility of pregnant USMC, providing new insights into the molecular mechanisms underlying regional differences in uterine contractility during pregnancy.

Keywords: Ferroptosis; Hypoxia; Mitochondrion; Pregnant rat; Uterus contraction.

摘要

妊娠期子宫收缩力的区域性差异已得到充分证实。然而，这些差异的分子机制仍不清楚。为了解决这个问题，我们对妊娠大鼠的子宫进行了等张收缩实验，结果发现胎盘附着侧的子宫收缩力明显低于非附着侧。有趣的是，胎盘附着组织的乳酸累积量更高，这表明这些区域之间存在代谢差异。肌肉收缩需要大量能量，三磷酸腺苷（ATP）是能量的直接来源，主要由细胞能量生产中心线粒体提供。线粒体能量的产生在很大程度上依赖于氧气的供应。为了探索氧气条件对子宫平滑肌细胞（USMC）收缩的影响，我们在缺氧条件下培养了这些细胞。结果发现，缺氧会降低细胞的收缩能力并破坏线粒体的完整性。具体来说，线粒体表现出收缩和变形，其特征是嵴减少和线粒体膜电位崩溃。这些结构和功能变化与铁凋亡的特征一致。此外，缺氧刺激动态相关蛋白 1（Drp1）向线粒体转位，这一过程与线粒体破碎有关。当 Drp1 的活性受到抑制时，铁凋亡就会减弱，这突出了它在这一过程中的调节作用。总之，这些研究结果表明，缺氧诱导的铁蛋白沉积会损害线粒体，导致能量生成和细胞活力降低。这最终降低了妊娠美国海军陆战队的收缩力，为了解妊娠期间子宫收缩力区域差异的分子机制提供了新的视角。

关键词: 缺氧；线粒体；妊娠大鼠；子宫收缩