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J. Shen, X.-R. Yang, B. Xie, W.-H. Xiao, Y.-J. Chen, M. Swaim, P. Campochiaro; Regulation of Retinal Neovascularization by microRNA. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4057.
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The purpose of this study was to determine if microRNAs participate in regulation of retinal neovascularization.
Small RNA species isolated from P15 retinas of mice with oxygen-induced ischemic retinopathy were used as probes in microRNA arrays. Array data were verified by real-time PCR. Possible target sequences of down-regulated microRNAs were identified by bioinformatic techniques and tested in microRNA reporter arrays. The effect of intraocular injection of precursor microRNAs was assessed in models of retinal and choroidal neovascularization.
Compared to control retinas, levels of 77 microRNAs were significantly altered in retinas of mice with ischemic retinopathy; 3 microRNAs were reduced by at least 1 log unit. Over forty 3’-UTR sequences of angiogenic factors were analyzed for 7 base pair complementary matches with purported seed regions at the 5’ end of the 3 down-regulated microRNAs. At least one target site was identified in the 3’-UTR area of Vegf, Pdgfb Hif1α, Notch4, and Frizzled4. Testing of these sequences in a microRNA reporter assay using the precursor microRNA with complementary sequence for each, confirmed that all were target sequences except the one in Notch4 3’-UTR. Intravitreous injection of the microRNA targeting Vegf, Pdgfb, or Hif1α at P12 in mice with ischemic retinopathy resulted significant reduction in protein level for each and suppressed retinal neovascularization. Intravitreous injection of each of these 3 microRNAs also suppressed choroidal neovascularization at Bruch’s membrane rupture sites.
These data suggest that down-regulation of microRNAs that target Vegf, Pdgfb, or Hif1α may contribute to retinal neovascularization and increasing their levels in retinal cells could provide the basis for a new treatment approach for retinal and choroidal neovascularization.
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