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Chi-Hsiu Liu, Ye Sun, Jie Li, Lucy Evans, Katherine Tian, Thomas Fredrick, Nicholas Saba, Peyton Morss, Jing Chen; Modulation of endothelial cell function and pathologic ocular angiogenesis by microRNA-150. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5851.
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© ARVO (1962-2015); The Authors (2016-present)
Pathologic ocular angiogenesis is a major cause of blindness in several vascular eye diseases. In order to develop effective targeted therapeutics, it is critical to define factors dysregulated in pathologic neovessels. MicroRNAs are small non-coding RNAs regulating gene expression at the post-transcriptional level, and may mediate pathologic angiogenesis. Here we investigated the potential role of a specific microRNA, miR-150, in regulating ocular angiogenesis.
Two mouse models of pathologic ocular angiogenesis were used: the oxygen-induced retinopathy (OIR) and the laser-induced choroidal neovascularization (CNV). In OIR, neonatal mice were exposed to 75% O2 from postnatal day 7 to 12. MicroRNA array was performed with OIR retinas compared with normoxic controls, followed by verification with RT-PCR and localization with laser capture microdissected (LCM) retinal neural and vascular layers. Pathologic retinal neovascularization (NV) in OIR was quantified in miR-150 knockout (miR-150-/-) and wild type (WT) mice, and WT mice injected intravitreally with miR-150 mimic and negative control. For CNV model, adult miR-150-/- and WT mice were treated with laser photocoagulation and CNV lesions were analyzed at 1 week post laser. Effects of miR-150 on endothelial cell function were analyzed in human retinal microvascular endothelial cells (HRMECs). Putative target genes of MiR-150 were validated in both retinas and HRMECs.
Expression of miR-150 was found highly enriched in LCM retinal blood vessels isolated from normal retinas compared with retinal neurons, and significantly suppressed in pathologic NV isolated from OIR retinas. OIR-treated miR-150-/- retinas revealed increased retinal NV compared with WT. Intravitreal injection of miR-150 mimic significantly decreased NV in OIR. In laser-induced CNV, miR150-/- mice showed significantly larger CNV lesions compared with WT. HRMECs treated with miR-150 mimic revealed substantially decreased levels of cell proliferation, migration, and tubular formation. Loss of miR-150 led to strong upregulation of predicted target angiogenic genes (Cxcr4, Dll4, Fzd4, Plxnd1, and Kdr) in OIR retinas in vivo and in HRMECs in vitro.
Our findings indicate that vascular-enriched miR-150 is a novel endogenous inhibitor of pathologic ocular NV. MiR-150 may represent a potential therapeutic target to develop treatments for neovascular eye diseases.
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