Angiogenin-driven rRNA transcriptional activation regulates endometrial receptivity through epithelial remodeling

Endometrial receptivity is crucial for successful embryo implantation and the establishment of pregnancy. Although exogenous gonadotropin-controlled ovarian stimulation (OS) is widely used in assisted reproductive technology to induce multiple ovulations, it has been linked to impaired endometrial receptivity, and effective interventions remain limited. In this study, we demonstrate that OS disrupts endometrial receptivity in mice by interfering with epithelial remodeling, manifested as downregulation of tight junctions, aberrant epithelial proliferation, reduced adhesion, and abnormal epithelial morphology. Moreover, OS induced upregulation of angiogenin (Ang) in endometrial stromal cells, while its receptor was expressed in epithelial cells. Mechanistically, OS-elevated serum estradiol (E2) enhances Ang expression through ERα binding to the Ang promoter. In vitro, Ang disrupts the proliferation-differentiation balance in endometrial epithelial cells by enhancing rRNA transcription. Genetic deficiency of Ang attenuated OS-induced impairment of epithelial remodeling and restored normal epithelial architecture. Pharmacological inhibition of Ang with neomycin improved uterine receptivity, implantation rates, and fetal development in OS-treated mice. Collectively, our findings identify stromal-derived Ang as a critical mediator that regulates endometrial receptivity through activation of rRNA transcription. Targeting Ang signaling may represent a promising therapeutic strategy to improve endometrial receptivity and enhance in vitro fertilization outcomes.