Inhibition of retinal angiogenesis by peptides derived from thrombospondin-1.
OBJECTIVE
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)-beta1 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-beta1 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.
Shafiee
A
A
Department of Ophthalmology, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA.
Penn
J S
JS
Krutzsch
H C
HC
Inman
J K
JK
Roberts
D D
DD
Blake
D A
DA
D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D002417:Cattle; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015861:Retinal Neovascularization / Q000473:pathology / Q000517:prevention & control*; D012171:Retinal Vessels / Q000187:drug effects / Q000473:pathology; D012178:Retinopathy of Prematurity / Q000473:pathology / Q000517:prevention & control; D019700:Thrombospondin 1 / Q000494:pharmacology*; D013997:Time Factors
D010446:Peptide Fragments; D019700:Thrombospondin 1