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

Abstract

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.

Extracellular vesicles released from p18 overexpressing pulmonary endothelial cells are barrier protective – potential implications for acute respiratory distress syndrome

“…Whilst these miRNA have not been previously associated with vascular leak, miR-137-5p and miR-30a-5p are both linked to pro-angiogenic processed whilst miR-96-5p has been shown to be downregulated in settings of oxidative stress in ARPE-19 cells. 32 – 34 Interestingly, in the kidney and brain, let-7i-5p has been closely linked with anti-inflammatory processes in vitro and in vivo with elevated miRNA linked to decreased TLR4 expression and signaling. 35 , 36 Thus it is possible that EDEVs rich in let-7i-5p miRNA protect the pulmonary endothelium by reducing TLR4 expression, and thus reducing the ability of LPS to cause barrier disruption.…”

Deletion of Tgfβ signal in activated microglia prolongs hypoxia‐induced retinal neovascularization enhancing Igf1 expression and retinal leukostasis

“…To induce Cx3cr1-Cre recombination, 100 μg of tamoxifen (Sigma-Aldrich, T5648)/ cone oil solution was administered to Cx3cr1 CreÀERT ; Tgfbr2 flox/flox and control littermates, Tgfbr2 flox/flox (Control) subcutaneously once a day from P9 to P14 and for OIR P4 to P6 and P12 to P14 to avoid the oxygen level fluctuation in chamber from P7 to P12. Oxygen-induced retinopathy (OIR) was induced as previously described (Murinello et al, 2019;Smith et al, 1994). Postnatal day 7 (P7) pups and their mothers were exposed to 75% oxygen in a hyperoxia chamber (BioSpherix ProOx P110) for 5 days and returned to room air at P12.…”

Relevance of Peptide Homeostasis in Metabolic Retinal Degenerative Disorders: Curative Potential in Genetically Modified Mice

“…These models demonstrate how different pathways and mediators of the molecular cascade contribute to the manifestation of ischemia, with the main participants of the pathophysiology originating from the disturbance of the nutrient and oxygen supply. Different genetic approaches used here target vascular alterations ( Murinello et al, 2019 ; Bats et al, 2020 ; Gutsaeva et al, 2020 ; Villacampa et al, 2020 ), oxidative stress mediators ( Chan et al, 2012 ; Schultz et al, 2016 ), neuronal cell death ( Cervia et al, 2008b ; Zhu et al, 2013 ; Luo et al, 2021 ) and inflammation ( Portillo et al, 2008 ; Dvoriantchikova et al, 2014 ).…”