PGE2 and Thrombin Induce Myofibroblast Transdifferentiation via Activin A and CTGF in Endometrial Stromal Cells.

Abstract

Endometriosis is characterized by inflammation and fibrotic changes. Our previous study using a mouse model showed that proinflammatory factors present in peritoneal hemorrhage exacerbated inflammation in endometriosis-like grafts, at least in part through the activation of prostaglandin (PG) E2 receptor and protease-activated receptor (PAR). In addition, menstruation-related factors, PGE2 and thrombin (P/T), a PAR1 agonist induced epithelial-mesenchymal transition (EMT) of endometrial cells under hypoxia. However, the molecular mechanisms by which P/T induce development of endometriosis have not been fully characterized. To investigate the effects of P/T, RNA extracted from endometrial stromal cells (ESCs) treated with P/T were subjected to RNA sequence analysis, and identified activin A, FOS, and GATA2 as upregulated genes. Activin A increased the expression of connective tissue growth factor (CTGF) and mesenchymal marker genes in ESCs. CTGF induced the expression of fibrosis marker type I collagen, fibronectin, and α-smooth muscle actin (αSMA), indicating fibroblast to myofibroblast transdifferentiation (FMT) of ESCs. In addition, activin A, FOS, GATA2, CTGF, and αSMA were localized in endometriosis lesions. Taken together, our data show that P/T induces changes resembling EMT and FMT in ectopic ESCs derived from retrograde menstruation, and that these are associated with fibrotic changes in the lesions. Pharmacological means that block P/T-induced activin A and CTGF signaling may be strategies to inhibit fibrosis in endometriotic lesions.

• Authors: Kazuya Kusama, Yuta Fukushima, Kanoko Yoshida, Mana Azumi, Mikihiro Yoshie, Yumi Mizuno, Takeshi Kajihara, Kazuhiro Tamura
• Journal: Endocrinology (Endocrinology) Vol. 162 Issue 12 (12 01 2021) ISSN: 1945-7170 [Electronic] United States
• PMID: 34606582 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• activin A
• Activins
• Connective Tissue Growth Factor
• Thrombin
• Dinoprostone

Topics

• Activins (genetics, metabolism)
• Adult
• Cell Transdifferentiation (drug effects, genetics)
• Cells, Cultured
• Connective Tissue Growth Factor (genetics, metabolism)
• Dinoprostone (pharmacology)
• Endometriosis (pathology)
• Endometrium (cytology, drug effects, pathology)
• Female
• Humans
• Myofibroblasts (drug effects, physiology)
• Peritoneal Diseases (pathology)
• Signal Transduction (drug effects, genetics)
• Stromal Cells (drug effects, pathology, physiology)
• Thrombin (pharmacology)