Endoplasmic reticulum stress promotes endometrial fibrosis through the TGF-β/SMAD pathway

in Reproduction
Authors:
Meng BaoInstitute of Reproductive Health, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China

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https://orcid.org/0000-0002-9569-4695
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Qiwen FengInstitute of Reproductive Health, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China

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Liping ZouInstitute of Reproductive Health, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China

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https://orcid.org/0000-0003-0917-5344
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Jin HuangInstitute of Reproductive Health, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China

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Changhong ZhuInstitute of Reproductive Health, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China

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Wei XiaInstitute of Reproductive Health, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China

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Correspondence should be addressed to W Xia; Email: tjxiawei@hust.edu.cn
DOI:
https://doi.org/10.1530/REP-22-0294
Volume/Issue:
Volume 165: Issue 2
Page Range:
171–182
Article Type:
Research Article
Online Publication Date:
06 Jan 2023
Copyright:
© Society for Reproduction and Fertility 2023
Restricted access

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In brief

Intrauterine adhesion (IUA) is one of the main causes of female infertility. This study reveals that endoplasmic reticulum stress activation upregulates the TGF-β/SMAD pathway to induce epithelial–mesenchymal transition and promote endometrial fibrosis in an IUA model.

Abstract

IUA is a common gynecological disease and is a leading cause of female infertility. Mechanical or infectious damage to the endometrial basal layer can lead to endometrial fibrosis, which is the most common cause of IUA. Endoplasmic reticulum stress (ERS), the transforming growth factor beta signaling pathway (TGF-β/SMAD) and epithelial–mesenchymal transition (EMT) are important factors promoting endometrial fibrosis. The purpose of this study was to determine the up- and downstream regulatory relationships of the above three in the process of endometrial fibrosis. The rat IUA model was induced by double injury method and prophylactic injection of the ERS inhibitor 4-phenylbutyric acid (4-PBA) was given in vivo. The ERS activator tunicamycin and the TGF-β/SMAD pathway inhibitor A 83-01 were used in human endometrial epithelial cells (HEECs) in vitro. Masson’s trichrome, Sirius red staining, immunohistochemistry, immunofluorescence and Western blot analyses were used to determine ERS, TGF-β/SMAD pathway, EMT and fibrosis markers in the uterine tissue and HEECs of the different treatment groups. In animal experiments, ERS and the TGF-β/SMAD pathway had been activated and EMT occurred in an in vivo model of IUA but was suppressed in animals treated with prophylactic 4-PBA. In in vitro experiments, tunicamycin-treated HEECs had increased the activation of ERS, the abundance of TGF-β/SMAD pathway and fibrosis markers while EMT occurred, but the TGF-β/SMAD pathway and EMT were significantly inhibited in the tunicamycin+A 83-01 group. Our data suggest that increased ERS can induce EMT and promote endometrial fibrosis through the TGF-β/SMAD pathway.

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Print ISSN:
1470-1626
Online ISSN:
1741-7899

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