The hypoxia-mediated HIF-1α/miR-381-3p signaling pathway promotes retinal neovascularization.

Abstract

Retinal neovascularization is a common pathological feature of various retinal vascular diseases and is typically induced by hypoxia. In recent studies, the regulatory role of microRNA (miRNA)-mediated signaling in retinal neovascularization has been extensively characterized. However, although hypoxia-induced miRNA dysregulation has been identified, the specific mechanisms by which hypoxia modulates miRNAs in retinal neovascularization remain largely elusive. In this study, we first established a direct regulatory link between microRNA-381-3p (miR-381-3p) and hypoxia-inducible factor-1α (HIF-1α) using a dual-luciferase reporter gene assay. Based on an in vitro cellular hypoxia model and an in vivo oxygen-induced retinopathy (OIR) mouse model, we validated the regulatory effect of HIF-1α on miR-381-3p expression. In addition, downregulation of miR-381-3p attenuated retinal neovascularization, inflammation, and apoptosis in OIR mice. Transcriptome sequencing analysis identified Steap4, a differentially expressed gene, as a potential downstream target of miR-381-3p. Further detection suggested that inhibition of miR-381-3p expression could down-regulate the expression of STEAP4 both in vitro and in vivo. Collectively, our study provides compelling evidence that the HIF-1α/miR-381-3p pathway plays a critical regulatory role in retinal neovascularization, which complements the pathogenic mechanisms underlying retinal vascular diseases and suggests that miR-381-3p may serve as a potential therapeutic target for treating retinal neovascularization.