All‐Trans Retinoic Acid Promotes Endometrial Regeneration and Angiogenesis Associated With Wnt/β‐Catenin Signaling in a Mouse Model of Intrauterine Adhesion

Objective To investigate the therapeutic effects of all‐trans retinoic acid (ATRA) on endometrial repair and the underlying mechanisms. Methods We investigated the regenerative effects of ATRA in a chemically induced murine model of intrauterine adhesion (IUA) through histological evaluation, angiogenesis‐related analyses, hormone receptor assessment, and fertility testing. We further explored the potential involvement of Wnt/β‐catenin signaling in ATRA‐mediated endometrial repair using the pharmacological inhibitor XAV939. Results All‐trans retinoic acid (ATRA) administration significantly improved uterine morphology, as evidenced by increased endometrial thickness and glandular number. In parallel, ATRA markedly enhanced the expression of angiogenesis‐related markers, including platelet endothelial cell adhesion molecule‐1 (CD31), vascular endothelial growth factor A (VEGFA), and vascular endothelial growth factor receptor 1 (VEGFR1), and restored estrogen receptor α (ER‐α) and progesterone receptor (PR) expression. Functional fertility testing further demonstrated improved embryo implantation and late‐stage fetal survival rate following ATRA treatment. Mechanistically, ATRA treatment was accompanied by enhanced Wnt/β‐catenin signaling activity, as evidenced by increased phosphorylation of β‐catenin (Ser675) and upregulation of the downstream target genes Axin2 and c‐Myc . Moreover, pharmacological inhibition of Wnt/β‐catenin signaling with XAV939 partially attenuated the regenerative and proangiogenic effects of ATRA. Conclusion These findings suggest that ATRA may promote endometrial regeneration and improve reproductive outcomes in IUA, at least in part through the modulation of angiogenesis and Wnt/β‐catenin signaling.