Fibronectin Mediates Endothelial-to-Mesenchymal Transition in Retina Angiogenesis

Abstract

PURPOSE. The purpose of this study was to investigate the role of endothelial-mesenchymal transition (EndoMT) in pathological retinal angiogenesis and identify key molecular mediators in retina angiogenesis. METHODS. RNA sequencing (RNA-seq) was performed on retinal tissue from an oxygen-induced retinopathy (OIR) mouse model to analyze gene expression patterns. The Gene Set Enrichment Analysis was used to examine the correlation between epithelial-mesenchymal transition (EMT) and angiogenesis gene sets. Fibronectin (FN1) expression was evaluated in endothelial cells, and its function was assessed through siRNA-mediated knockdown in both in vitro angiogenesis assays and the OIR model. RESULTS. EndoMT occurred early in retinal angiogenesis development, with significant correlation between EMT and angiogenesis gene sets. FN1 was identified as the most significantly upregulated EMT-related gene in endothelial cells. The siRNA-mediated inhibition of fibronectin effectively prevented VEGF-induced angiogenesis in vitro and reduced pathological angiogenesis in the OIR model. CONCLUSIONS. EndoMT is a crucial early event in pathological retinal angiogenesis, with fibronectin serving as a key mediator. Targeting fibronectin may provide a novel therapeutic strategy that could synergize with anti-VEGF treatments to more effectively treat pathological angiogenesis in diabetic retinopathy (DR) and retinopathy of prematurity (ROP), particularly in cases of poor response to anti-VEGF therapy alone.