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Inhibition of retinal angiogenesis by peptides derived from thrombospondin-1
A Shafiee1, J S Penn, H C Krutzsch
1Department of Ophthalmology, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA.
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)-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.
Insights
Thrombospondin-1 (TSP-1) and its derived peptides show potential for treating retinal angiogenesis. Specific TSP-1 peptide sequences effectively inhibit neovascularization in experimental models, suggesting therapeutic applications.
Area of Science:
- Ophthalmology
- Molecular Biology
- Oncology
Background:
- Thrombospondin-1 (TSP-1) is a known tumor suppressor.
- TSP-1 exhibits anti-angiogenic properties by inhibiting neovascularization.
- Previous research localized this activity to TSP-1's type 1 repeats and amino-terminal procollagen-like domain.
Purpose of the Study:
- To investigate the anti-angiogenic potential of TSP-1 and its derived peptides.
- To evaluate TSP-1's ability to inhibit retinal angiogenesis.
- To identify specific peptide sequences within TSP-1 responsible for anti-angiogenic activity.
Main Methods:
- Utilized two models of retinal angiogenesis: a retinal explant assay and a rat model of retinopathy of prematurity (ROP).
- Tested full-length TSP-1 and synthetic peptides containing tryptophan-rich, heparin-binding, and TGF-beta1 activation sequences.
- Assessed the inhibitory effects of TSP-1 and peptides on endothelial cell outgrowth and neovascular disease.
Main Results:
- Platelet-derived TSP-1 demonstrated significant inhibition of angiogenesis in both experimental models.
- Peptides combining tryptophan-rich and TGF-beta1 activation sequences were potent inhibitors of endothelial cell outgrowth in the explant assay.
- A peptide with only the tryptophan-rich, heparin-binding sequence was most effective in reducing neovascular disease in the ROP model.
Conclusions:
- TSP-1's type 1 repeats contain distinct subdomains that independently regulate neovascularization.
- Peptides derived from TSP-1's type 1 repeats show promise as pharmacologic agents.
- These findings suggest potential therapeutic strategies for treating retinal angiogenesis.