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Sudhakar Akulapalli, Venugopal Gunda, Archana Laknaur, Boosani C. Shekhar; Mechanism of Regulation of Laser Induced Choroidal Neovascularisation by Tumstatin. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1794.
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Choroidal neovascularisation is the primary cause of blindness in a variety of common retinal diseases including retinopathy of prematurity, age related macular degeneration, proliferative diabetic retinopathy, among other vascular diseases. Angioinhibitory therapies are starting to give hopeful results in these ocular diseases. In this study the angioinhibitory activity of tumstatin was analyzed in-vitro with mouse choroidal endothelial cell proliferation, migration and tube formation assays. Tumstatin adenovirus was also tested in-vivo in the laser-induced choroidal neovascularisation.
Mouse choroidal endothelial cells were prepared and treated with tumstatin and in-vitro proliferation, migration and tube formation assays were performed. Matrix metalloproteinase-2 (MMP-2) activation and MMP-2/tumstatin complex formation were studied using gelatin zymography, Immunobloting and ISCO gradient analysis. Also evaluated the angioinhibitory effects of tumstatin adenoviruses in-vitro using laser induced choroidal neovascularisation in mice model.
Tumstatin demonstrated anti-proliferative activity and inhibits MCEC invasion, tube formation in-vitro. Tumstatin binds to collagen binding domain (CBD) of MMP-2 and inhibits its activation mediated by both membrane-type-1 MMP (MT1-MMP) and 4-amino-phenyl mercuric acetate (APMA) in-vitro. Adenoviruses secreted tumstatin also confirmed that significant inhibition of laser induced CNV in mice and circulating MMP-2 activation in-vivo.
The mechanism of angioinhibitory effect of tumstatin on choroidal neovascularisation was found in-vitro and in-vivo. The identification of useful and potent endogenous angioinhibitors like tumstatin provides insight into the pathogenesis of choroidal neovascularisation. These results validate the potentiality of tumstatin in therapeutic applications for prevention of ocular diseases.
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