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A short peptide domain of platelet factor 4 blocks angiogenic key events induced by FGF‐2

Platelet factor 4 (PF‐4) is a CXC‐chemokine with strong anti‐angiogenic properties. We have shown previously that PF‐4 inhibits angiogenesis by associating directly with fibroblast growth factor 2 (FGF‐2), inhibiting its dimerization, and blocking FGF‐2 binding to endothelial cells. We now have characterized a small peptide domain (PF‐447–70) derived from the C‐terminus of PF‐4, which conserves anti‐angiogenic effects of the parent protein. PF‐447‐70 inhibited internalization of 125I‐FGF‐2 by endothelial cells in a time‐dependent manner. The peptide reduced FGF‐2‐stimulated cell migration to control levels in wounded monolayers of bovine capillary endothelial cells. PF‐447–70 also reduced FGF‐2 induced phosphorylation of MAP kinases ERK‐1 and ERK‐2, which are essential for migration and survival of endothelial cells. In a serum‐free exvivo angiogenesis assay, the peptide blocked microvessel outgrowth by 89%. A single amino acid substitution within PF‐447–70 abolished all inhibitory activities. To simulate a real anti‐angiogenic treatment situation, we administered PF‐447–70 systemically to mice implanted subcutaneously with FGF‐2 containing gelatin sponges with the result of sparse, scattered, and immature vessel growth. The small peptide fragment derived from the angioinhibitory CXC‐chemokine PF‐4 might be used as a starting point to develop anti‐angiogenic designer drugs for angiogenesis‐dependent pathologies such as cancer, diabetic retinopathy, and rheumatoid arthritis.