2. Academic Validation
  3. Endothelial senescence induced by PAI-1 promotes endometrial fibrosis

Endothelial senescence induced by PAI-1 promotes endometrial fibrosis

  • Cell Death Discov. 2025 Mar 6;11(1):89. doi: 10.1038/s41420-025-02377-0.
Jing Wu 1,  Jie Wang 1,  Zhongrui Pei 1,  Yaru Zhu 1,  Xier Zhang 1,  Zihan Zhou 2,  Chunying Ye 1,  Minmin Song 3,  Yali Hu 4,  Pingping Xue 5,  Guangfeng Zhao 6 7
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China.
  • 2 Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
  • 3 Obstetrics and Gynaecology Hospital, Fudan University, Shanghai, China.
  • 4 Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. yalihu@nju.edu.cn.
  • 5 Department of Reproductive Medicine Center, Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, China. 13616118039@163.com.
  • 6 Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China. zhaoguangfeng@nju.edu.cn.
  • 7 Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. zhaoguangfeng@nju.edu.cn.
PMID: 40050610 DOI: 10.1038/s41420-025-02377-0
Abstract

Intrauterine adhesions (IUAs), also known as Asherman's syndrome (AS), represent a significant cause of uterine infertility for which effective treatment remains elusive. The endometrium's ability to regenerate cyclically depends heavily on the growth and regression of its blood vessels. However, trauma to the endometrial basal layer can disrupt the subepithelial capillary plexus, impeding regeneration. This damage results in the replacement of native cells with fibroblasts and myofibroblasts, ultimately leading to fibrosis. Endothelial cells (ECs) play a pivotal role in the vascular system, extending beyond their traditional barrier function. Through single-cell Sequencing and experimental validation, we discovered that ECs undergo senescence in IUA patients, impairing angiogenesis and fostering stromal cell fibrosis. Further analysis revealed significant interactions between ECs and PAI-1+ stromal cells. PAI-1, derived from stromal cells, promotes EC senescence via the urokinase-type plasminogen activator receptor (uPAR). Notably, prior to fibrosis onset, TGF-β upregulates PAI-1 expression in stromal cells in a SMAD dependent manner. In an IUA mouse model, inhibiting PAI-1 mitigated EC senescence and endometrial fibrosis. Our findings underscore the crucial role of EC senescence in IUA pathogenesis, contributing to vascular reduction and fibrosis. Targeting PAI-1 represents a promising therapeutic strategy to suppress EC senescence and alleviate endometrial fibrosis, offering new insights into the treatment of IUAs.

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