miR‐30a‐5p inhibition promotes interaction of Fas+ endothelial cells and FasL+ microglia to decrease pathological neovascularization and promote physiological angiogenesis

Ischemia‐induced angiogenesis contributes to various neuronal and retinal diseases, and often results in neurodegeneration and visual impairment. Current treatments involve the use of anti‐VEGF agents but are not successful in all cases. In this study we determined that miR‐30a‐5p is another important mediator of retinal angiogenesis. Using a rodent model of ischemic retinopathy, we show that inhibiting miR‐30a‐5p reduces neovascularization and promotes tissue repair, through modulation of microglial and endothelial cell cross‐talk. miR‐30a‐5p inhibition results in increased expression of the death receptor Fas and CCL2, to decrease endothelial cell survival and promote microglial migration and phagocytic function in focal regions of ischemic injury. Our data suggest that miR‐30a‐5p inhibition accelerates tissue repair by enhancing FasL–Fas crosstalk between microglia and endothelial cells, to promote endothelial cell apoptosis and removal of dead endothelial cells. Finally, we found that miR‐30a levels were increased in the vitreous of patients with proliferative diabetic retinopathy. Our study identifies a role for miR‐30a in the pathogenesis of neovascular retinal disease by modulating microglial and endothelial cell function, and suggests it may be a therapeutic target to treat ischemia‐mediated conditions. Main Points miR‐30a inhibition potently inhibits angiogenesis by targeting the death receptor Fas. miR‐30a also regulates microglia migration and phagocytosis by targeting CCL2. miR‐30a levels are elevated in the vitreous of diabetic patients with retinopathy.