Inhibition of retinal angiogenesis by peptides derived from thrombospondin-1

PURPOSE. Thrombospondin (TSP)-1 is a tumor suppressor with activity that is associated with its ability to inhibit neovascularization. Previous studie s have mapped this antiangiogenic activity to the type 1 repeats and the am ino-terminal portion of the molecule within the procollagen-like domain. Th e present study was performed to investigate the ability of TSP-1 and pepti des 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)-beta 1 activation sequences were eval uated 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-beta 1 activation sequence, were the mos t potent inhibitors of endothelial cell outgrowth in the retinal explant as say. In contrast, a peptide containing only the tryptophan-rich, heparin-bi nding 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 contai n two subdomains that may independently influence the process of neovascula rization, and that peptides derived from these type 1 repeats may be promis ing pharmacologic agents for treatment of retinal angiogenesis.