All-Trans Retinoic Acid Modulates MicroRNA-129-5p/Hypoxia-Inducible Factor-1α/Vascular Endothelial Growth Factor Signaling and Suppresses Ets-1 in Retinal Pigment Epithelial ARPE-19 Cells.

Purpose: Proliferative vitreoretinopathy (PVR) is a vision-threatening complication of retinal detachment or ocular trauma characterized by the formation of contractile fibrotic membranes. Retinal pigment epithelium (RPE) cells are central to PVR pathogenesis, driving maladaptive wound-healing responses. This study investigated the effects of all-trans retinoic acid (ATRA) on RPE cell proliferation, vascular endothelial growth factor (VEGF) secretion, and miR-129-5p biogenesis, alongside the downstream regulation of Ets-1 and the hypoxia-inducible factor-1α (HIF-1α)/VEGF axis.Methods: Human ARPE-19 cells were treated with ATRA under quiescent or protein kinase C (PKC)-activated conditions. Proliferation, VEGF secretion, and miR-129-5p expression were quantified via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, enzyme-linked immunosorbent assay, and real-time quantitative PCR. Bioinformatic analysis, miR-129-5p mimic transfection, Western blotting, and protein ubiquitination assays were utilized to characterize the regulatory mechanisms.Results: ATRA exerted a dose- and time-dependent cytostatic effect on ARPE-19 cells without inducing cytotoxicity. VEGF modulation was highly context-dependent: basal secretion exhibited a biphasic response (peaking at 10-7 M), whereas PKC-stimulated secretion was significantly suppressed. Mechanistically, ATRA promoted intracellular miR-129-5p accumulation, which directly silenced the profibrotic factor Ets-1. Paradoxically, miR-129-5p mimic transfection stabilized HIF-1α protein by reducing its polyubiquitination, thereby enhancing VEGF production.Conclusions: Our findings characterize miR-129-5p as a pivotal molecular switch orchestrating ATRA-mediated RPE modulation. By decoupling antifibrotic activity (Ets-1 suppression) from cytoprotective signaling (HIF-1α stabilization), this miR-129-5p/HIF-1α/VEGF axis balances the attenuation of pathological fibrosis with the preservation of homeostatic survival factors for retinal integrity, providing a nuanced therapeutic approach for PVR and the associated retinal disorders.