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  • Mare endometrium fibrosis : epigenetics and novel fibrosis markers
    Publication . Alpoim-Moreira, Joana; Dias, Graça Maria Leitão Ferreira; Crisóstomo, Maria Rosa Rebordão Cordeiro Simões
    ABSTRACT - Endometrosis is a major cause of infertility in mares and involves the excessive deposition of extracellular matrix (ECM) in the mare's endometrium, such as collagen type I (COL1), and type III (COL3). In fibrosis there is an imbalance between metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), resulting in dysregulation between collagen degradation and deposition. Transforming growth factor β1 (TGF-β1) is one of the major pro fibrotic signals for myofibroblast differentiation, identified by the expression of α-smooth muscle actin (α-SMA), promoting collagen production. Alterations in fibroblast phenotype are associated with epigenetic alterations in chromatin structure. Epigenetic changes can be reversed and therefore extremely promising for therapeutic use. DNA methylation analysis is one of the most used methods to detect epigenetic changes. The aims of this study were to: (i) evaluate if COL1, COL3 and hydroxyproline could serve as possible blood biomarkers of equine endometrosis diagnosis and fertility assessment; (ii) evaluate the existence of a possible correlation between mRNA levels of DNA methyltransferases (DNMTs) and COL1A2 or COL3A1 in different Kenney and Doig’s endometrial categories and at different estrous cycle phases; (iii) evaluate the transcription and locus specific DNA methylation of COL1A1, COL1A2, COL3A1, MMP2, MMP9, TIMP1, and TIMP2 in different mare endometrial categories; (iv) investigate the in vitro epigenetic regulation in endometrial fibroblasts challenged with TGF-β1 and to assess the use of the epigenetic modifier, 5-aza-2′- deoxycytidine (5-aza-dC or decitabine), on endometrial fibroblasts exposed to profibrotic TGF-β1. Serum COL3 concentrations increased with more advanced Kenney and Doig´s endometrial categories. Serum COL3 concentration was also higher in infertile mares, when compared to fertile mares. Both sensibility and specificity of COL3 was most effective to differentiate mares from category I from all other categories. Only COL3 proved to be a possible biomarker of mare endometrial fibrosis. Concerning epigenetic studies, DNMT3B increased with endometrial category grade, and it was independent of estrous cycle phase. There were lower transcription levels of MMP2 and MMP9, simultaneously with higher DNA methylation percentage, in higher endometrial categories. The demethylating drug 5-aza-dC reduced the collagen expression (mRNA and protein) in TGF-β1 treated endometrial fibroblasts. A different approach via epigenetics may provide an alternative means to address mare endometrial fibrosis and a more in-depth knowledge of the pathophysiology of this condition
    2023-05-17Doctoral thesis Open access Show more