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Overexpression of miR-181a-5p inhibits retinal neovascularization through endocan and the ERK1/2 signaling pathway.

ABSTRACT: Retinal neovascularization (RNV) is a common pathological feature of angiogenesis-related retinopathy. Endocan inhibition has previously been reported to suppress RNV in oxygen-induced retinopathy (OIR); however, its molecular mechanisms remain to be elucidated. Here, we investigated the role and mechanism of endocan in OIR. We established an OIR mouse model and detected aberrant endocan overexpression in OIR mouse retinas. Endocan inhibition through small interfering RNA or a neutralizing antibody inhibited vascular endothelial growth factor-induced cell survival, cell proliferation, and tube formation in human retinal endothelial cells in vitro and reduced the RNV area in vivo. Using RNA sequencing, a luciferase reporter assay, and bioinformatics analyses, we identified endocan as a microRNA-181a-5p target gene. The antiangiogenic effect of miR-181a-5p on RNV was verified by intravitreal injection, and we showed that this involved the extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) signaling pathway. Collectively, our data demonstrate that miR-181a-5p/endocan regulates retinal angiogenesis through the ERK1/2 signaling pathway and might represent an attractive therapeutic strategy for RNV.

SUBMITTER: Chen X

PROVIDER: S-EPMC7587009 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Overexpression of miR-181a-5p inhibits retinal neovascularization through endocan and the ERK1/2 signaling pathway.

Chen Xiuping X Yao Yiyun Y Yuan Fei F Xie Bing B

Journal of cellular physiology 20200428 12

Retinal neovascularization (RNV) is a common pathological feature of angiogenesis-related retinopathy. Endocan inhibition has previously been reported to suppress RNV in oxygen-induced retinopathy (OIR); however, its molecular mechanisms remain to be elucidated. Here, we investigated the role and mechanism of endocan in OIR. We established an OIR mouse model and detected aberrant endocan overexpression in OIR mouse retinas. Endocan inhibition through small interfering RNA or a neutralizing antib ...[more]

PMID: 32346884

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Project description:The present study aimed to investigate the significant role of ?-elemene in mouse models of oxygen-induced retinopathy (OIR). C57BL/6J neonatal mice were used to establish OIR models. They were divided into four groups: Normoxia, OIR, OIR control and OIR?treated. Mice in the OIR group were exposed to 75±5% oxygen for 5 days and returned to a normal oxygen environment on postnatal day 12 (P12). The OIR treated group was intravitreally injected with 1 µl ??elemene on P12 and subsequently returned to a normal oxygen environment for 5 days (P12?P17). Retinas were obtained on P17. Retinal neovascularization (RNV) was detected using adenosine diphosphatase staining and analyzed by counting the nuclei of neovascular endothelial cells. Vascular endothelial growth factor (VEGF) expression was determined by reverse transcription?quantitative polymerase chain reaction, immunohistochemistry and western blot analysis. MicroRNA (miRNA/miR) microarrays were used to screen out differentially expressed miRNAs between the OIR and ??elemene?treated groups. Binding the 3'?untranslated region (UTR) of VEGF and miR?27a was confirmed using luciferase assays. It was found that high oxygen concentrations accelerated RNV and increased the number of preretinal neovascular cells; ??elemene treatment reduced these effects. VEGF mRNA and protein expression was higher in the OIR and OIR control groups, compared with the normoxia and OIR?treated groups. Further, it was shown that miR?22, miR?181a?1, miR?335?5p, miR?669n, miR?190b, miR?27a and miR?93 were upregulated in the OIR?treated group, and downregulated in the OIR group. The prediction websites TargetScan and miRanda revealed that VEGF contained a potential miR?27a binding site in its 3'?untranslated region (UTR). Luciferase assays demonstrated that miR?27a directly bound to the 3'?UTR of VEGF. In vitro experiments demonstrated that miR?27a inhibited VEGF expression. In addition, ??elemene treatment upregulate miR?27a expression in vivo and in vitro. When miR?27a expression was depleted by miR?27a inhibitor, the protective effect of ??elemene on RNV was eliminated. The present study demonstrated that ??elemene reduced RNV in mouse OIR models via miR?27a upregulation, leading to reduced VEGF expression. This finding may contribute to the development of novel therapeutic strategies for human retinopathy.

Dataset Information

Overexpression of miR-181a-5p inhibits retinal neovascularization through endocan and the ERK1/2 signaling pathway.

Publications

Overexpression of miR-181a-5p inhibits retinal neovascularization through endocan and the ERK1/2 signaling pathway.

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