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Downregulation of endothelial microRNA-200b supports cutaneous wound angiogenesis by desilencing GATA binding protein 2 and vascular endothelial growth factor receptor 2.

ABSTRACT: MicroRNAs (miRs) regulate angiogenesis by posttranscriptional silencing of target genes. The significance of angiostatic miR-200b in switching on skin wound angiogenesis was tested.Wounding caused imminent and transient downregulation of miR-200b in dermal wound-edge endothelial cells. Derailing this injury response by lentiviral delivery of miR-200b in vivo impaired wound angiogenesis. Computational prediction, target reporter luciferase assay, and Western blot analysis provided first evidence that miR-200b targets globin transcription factor binding protein 2 (GATA2) and vascular endothelial growth factor receptor 2 (VEGFR2). Overexpression of GATA2 or VEGFR2 in endothelial cells rescued the angiostatic effect of miR-200b in vitro. Downregulation of miR-200b derepressed GATA2 and VEGFR2 expression to switch on wound angiogenesis, which was disrupted in diabetic wounds. Treatment of endothelial cells with tumor necrosis factor-?, a proinflammatory cytokine abundant in diabetic wounds, induced miR-200b expression, silenced GATA2 and VEGFR2, and suppressed angiogenesis. These outcomes were attenuated using anti-miR-200b strategy. Neutralization of tumor necrosis factor-? in the diabetic wounds improved wound angiogenesis and closure, which was accompanied by downregulation of miR-200b expression and desilencing of GATA2 and VEGFR2.Injury-induced repression of miR-200b turned on wound angiogenesis. In mice with diabetes mellitus,excessive tumor necrosis factor-? induced miR-200b blunting proangiogenic functions of GATA2 and VEGFR2.

SUBMITTER: Chan YC

PROVIDER: S-EPMC3399424 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Downregulation of endothelial microRNA-200b supports cutaneous wound angiogenesis by desilencing GATA binding protein 2 and vascular endothelial growth factor receptor 2.

Chan Yuk Cheung YC Roy Sashwati S Khanna Savita S Sen Chandan K CK

Arteriosclerosis, thrombosis, and vascular biology 20120412 6

<h4>Objective</h4>MicroRNAs (miRs) regulate angiogenesis by posttranscriptional silencing of target genes. The significance of angiostatic miR-200b in switching on skin wound angiogenesis was tested.<h4>Methods and results</h4>Wounding caused imminent and transient downregulation of miR-200b in dermal wound-edge endothelial cells. Derailing this injury response by lentiviral delivery of miR-200b in vivo impaired wound angiogenesis. Computational prediction, target reporter luciferase assay, and ...[more]

PMID: 22499991

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Project description:PurposeThe purpose of this study was to investigate the effects and mechanism of microRNA (miR)-92a-3p in retinal angiogenesis in vitro and in vivo.MethodsThe expression of miR-92a-3p was verified by real-time quantitative polymerase chain reaction (RT-qPCR). Agomir-92a-3p was intravitreally injected into the right eye on postnatal day 3 (P3), P5, and P8 in the mice, with the agomir-NC injected left eye as the control. At P7, P9, and P12, immunofluorescence was performed to examine the retinal superficial vascular plexus, deep vascular plexus, proliferation, and apoptosis in retinal vascular endothelial cells (ECs). Human retinal microvascular endothelial cells (HRMECs) were treated with mimic-NC and mimic-92a-3p, then the tube formation, cell migration, and wound healing assays were used to detect the effect of miR-92a-3p on retinal angiogenesis in vitro. Agomir-92a-3p was also intravitreally injected into the right eye of oxygen-induced retinopathy (OIR) mice at P12, with the agomir-NC injected left eye as the control, the neovascularization was observed by retinal flatmount staining with isolectin B4 at P17. Bioinformatics and high-throughput sequencing were performed to identify potential target genes of miR-92a-3p. RT-qPCR and Western blot were carried out to detect the expression of SGK3, p-GSK3β, GSK3β, Bcl-xL, and cleaved caspase-3 in the HRMECs and mouse retinas.ResultsThe overexpression of miR-92a-3p inhibited the development of retinal superficial vascular plexus and deep vascular plexus, decreased the expression of Ki67, and increased the expression of cleaved caspase-3 in isolectin B4-labeled retinal vascular ECs. In vitro, the overexpression of miR-92a-3p markedly suppressed the tube formation, cell migration, and wound healing of cultured ECs. Overexpression of miR-92a-3p inhibited both in vivo and in vitro physiological angiogenesis by downregulating the expression of SGK3, p-GSK3β/GSK3β, and Bcl-xL. In addition, agomir-92a-3p inhibited the pathological retinal neovascularization of OIR mice, by targeting SGK3, p-GSK3β/GSK3β, and Bcl-xL.ConclusionsThe miR-92a-3p could affect retinal angiogenesis by targeting SGK3 pathway, suggesting that miR-92a-3p may be a potential anti-angiogenic factor for retinal vascular disease.

Dataset Information

Downregulation of endothelial microRNA-200b supports cutaneous wound angiogenesis by desilencing GATA binding protein 2 and vascular endothelial growth factor receptor 2.

Publications

Downregulation of endothelial microRNA-200b supports cutaneous wound angiogenesis by desilencing GATA binding protein 2 and vascular endothelial growth factor receptor 2.

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