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Shusheng Wang; A dual function for miR-126 in choroidal neovascularization. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):43.
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© ARVO (1962-2015); The Authors (2016-present)
Studies from our lab and others have shown that microRNAs (miRNAs or miRs) are pivotal modulators of vascular development and disease. Particularly, using the miR-126 knockout mice we generated, we have found that miR-126 is required for angiogenesis and vascular integrity in vivo. The purpose of the current study is to characterize the retinal phenotype of miR-126 knockout mice, as well testing the effect of miR-126 overexpression and knockdown in a laser-induced choroidal neovascularization (CNV) model. We hypothesize that miR-126 has cell-type specific functions based on the expression level of its regulated genes in different cell types.
Knockout mice, laser injury AMD model, in vivo miRNA mimic and anti-miR delivery methods, as well as in vitro systems using retinal pigment epithelial cells (RPE) and endothelial cells (EC) were used to dissect the function of miR-126 in retinal vascular development and CNV.<br />
Our results provide evidence for a critical role for miR-126 in retinal vascular development but dual function of miR-126 in CNV. miR-126 knockout mice showed significant delay in postnatal retinal vascular sprouting, and displayed focal choroidal deficiency in the adults. Both inhibition of miR-126 expression by LNA-antimiR and overexpression of miR-126 by miRNA mimic repressed laser-induced CNV. To dissect the mechanism underlying the phenotype, we found that miR-126 is highly expressed in the EC cells, but also lowly in the RPE cells. In ECs, we have shown that miR-126 is required for MAPK and AKT signaling in response to angiogenic factors. However, in RPE cells, miR-126 targets VEGF by two independent mechanisms. Overexpression of miR-126 in RPE cells repressed the promoter activity and therefore the expression of αB-Crystallin, which in turn repressed VEGF protein level. miR-126 also targeted VEGF 3’-untranslated region, therefore directly repressed VEGF protein synthesis. Overexpression of miR-126 mimic repressed VEGF expression in the RPE cells, at least partly accounting for the surprising phenotype of miR-126 overexpression.<br />
These findings demonstrate miR-126 has dual function in ocular angiogenesis due to the differential expression level of miR-126 and its regulated genes in EC and RPE cells, suggesting a cell-type specific function of miR-126 in the mouse retina.
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