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1 From the Department of Ophthalmology, Tulane University School of Medicine, New Orleans, Louisiana; the 2 Department of Ophthalmology and Visual Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee; and the 3 Laboratory of Pathology, National Cancer Institute and National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
PURPOSE. Thrombospondin (TSP)-1 is a tumor suppressor with activity that is associated with its ability to inhibit neovascularization. Previous studies have mapped this antiangiogenic activity to the type 1 repeats and the amino-terminal portion of the molecule within the procollagen-like domain. The present study was performed to investigate the ability of TSP-1 and peptides derived from the type 1 repeats to inhibit retinal angiogenesis.
METHODS. TSP-1 and peptides with tryptophan-rich, heparin-binding sequences and transforming growth factor (TGF)-ß1 activation sequences were evaluated in two models of retinal angiogenesis: a retinal explant assay and a rat model of retinopathy of prematurity (ROP).
RESULTS. Platelet-derived TSP-1 inhibited angiogenesis in both experimental models. Peptides from the native TSP-1 sequence, which contained both the tryptophan-rich repeat and the TGF-ß1 activation sequence, were the most potent inhibitors of endothelial cell outgrowth in the retinal explant assay. In contrast, a peptide containing only the tryptophan-rich, heparin-binding sequence was most active in inhibiting neovascular disease in the rat ROP model.
CONCLUSIONS. These results indicate that the type 1 repeats of TSP-1 contain two subdomains that may independently influence the process of neovascularization, and that peptides derived from these type 1 repeats may be promising pharmacologic agents for treatment of retinal angiogenesis.
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