Ding Shuning, Hu Yunyun, Mao Peiyu, Lin Qiu, Yao Zhitao
The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China.
Department of Gynaecology and Obstetrics, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China.
Curr Mol Med. 2024;24(4):516-523. doi: 10.2174/1566524023666230420085743.
Intrauterine adhesion (IUA) caused by endometrial mechanical injury has been found as a substantial risk factor for female infertility (e.g., induced abortion). Estrogen is a classic drug for the repair of endometrial injury, but its action mechanism in the clinical application of endometrial fibrosis is still unclear.
To explore the specific action mechanism of estrogen treatment on IUA.
The IUA model and the isolated endometrial stromal cells (ESCs) model were built. Then CCK8 assay, Real-Time PCR, Western Blot and Dual- Luciferase Reporter Gene assay were applied to determine the targeting action of estrogen on ESCs.
It was found that 17β-estradiol inhibited fibrosis of ESCs by down-regulating miR-21-5p level and activating PPARα signaling. Mechanistically, miR-21-5p significantly reduced the inhibitory effect of 17β-estradiol on fibrotic ESCs (ESCs-F) and its maker protein (e.g., α-SMA, collagen I, and fibronectin), where targeting to PPARα 3'- UTR and blocked its activation and transcription, thus lowering expressions of fatty acid oxidation (FAO) associated key enzyme, provoking fatty accumulation and reactive oxygen species (ROS) production, resulting in endometrial fibrosis. Nevertheless, the PPARα agonist caffeic acid counteracted the facilitation action of miR-21-5p on ESCs-F, which is consistent with the efficacy of estrogen intervention.
In brief, the above findings revealed that the miR-21-5p/PPARα signal axis played an important role in the fibrosis of endometrial mechanical injury and suggested that estrogen might be a promising agent for its progression.
子宫内膜机械性损伤所致的宫腔粘连（IUA）已被发现是女性不孕（如人工流产）的一个重要危险因素。雌激素是修复子宫内膜损伤的经典药物，但其在子宫内膜纤维化临床应用中的作用机制仍不清楚。
探讨雌激素治疗IUA的具体作用机制。
建立IUA模型和分离的子宫内膜基质细胞（ESCs）模型。然后应用CCK8法、实时荧光定量PCR、蛋白质免疫印迹法和双荧光素酶报告基因检测法来确定雌激素对ESCs的靶向作用。
发现17β-雌二醇通过下调miR-21-5p水平和激活PPARα信号通路抑制ESCs纤维化。机制上，miR-21-5p显著降低17β-雌二醇对纤维化ESCs（ESCs-F）及其标志物蛋白（如α-平滑肌肌动蛋白、I型胶原和纤连蛋白）的抑制作用，其靶向PPARα 3'-UTR并阻断其激活和转录，从而降低脂肪酸氧化（FAO）相关关键酶的表达，引发脂肪堆积和活性氧（ROS）产生，导致子宫内膜纤维化。然而，PPARα激动剂咖啡酸抵消了miR-21-5p对ESCs-F的促进作用，这与雌激素干预的效果一致。
简而言之，上述研究结果表明miR-21-5p/PPARα信号轴在子宫内膜机械性损伤纤维化中起重要作用，并提示雌激素可能是其进展的一种有前景的药物。
