Microglia-derived exosomal miR-31-5p promotes type 2 diabetic retinopathy by impairing physiological angiogenesis homeostasis.

Diabetic retinopathy (DR) is characterized by disruption of the retinal physiological vasculature. Impairment of physiological angiogenesis profoundly destabilizes the retinal microenvironment and ultimately leads to visual dysfunction. Current treatments, including anti-vascular endothelial growth factor (VEGF) and laser photocoagulation therapy, mainly slow disease progression by inhibiting pathological neovascularization. However, strategies to restore functional vascular networks and retinal homeostasis remain limited. Analysis of miRNA profiles in retinal tissue and plasma exosomes from DR patients revealed that miR-31-5p, enriched in microglia-derived exosomes, is markedly upregulated during DR progression and was closely associated with retinal microvascular injury and repair. In vitro experiments demonstrated that retinal microvascular endothelial cells efficiently internalize microglia-derived exosomes. Mechanistically, miR-31-5p disrupts vascular maturation and exacerbates microvascular dysfunction by suppressing flotillin-1 (FLOT1)/sphingosine kinase-1 (SPHK1)/sphingosine-1-phosphate (S1P)/VEGF/zona occludens-1 (ZO-1) signaling axis. Conversely, inhibition of miR-31-5p markedly restored physiological angiogenesis in retinal microvascular endothelial cells. In a DR mouse model, intravitreal injection of a miR-31-5p inhibitor similarly rescued FLOT1 expression in endothelial cells, promoted vascular regeneration, alleviated retinal inflammation and oxidative stress. This study clarifies a novel microglia-endothelial cell communication mechanism, in which microglia-derived exosomes deliver miR-31-5p to suppress the FLOT1/SPHK1/S1P/VEGF/ZO-1 signaling axis, thereby disrupting physiological retinal vascular remodeling. Targeting miR-31-5p may represent a potential therapeutic strategy to physiological angiogenesis homeostasis and slow DR progression.