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.