Histidine-rich glycoprotein (HRG) is a heparin-binding glycoprotein present in plasma at 100 μg/ml. A recent study revealed that HRG suppressed heparin-dependent basic fibroblast growth factor (bFGF)-induced angiogenesis. Additionally, we reported that high mobility group box 1 (HMGB1) in complex with heparin induces angiogenesis; therefore, we examined the effect of HRG on heparin-dependent HMGB1-induced angiogenesis in the present study. HRG completely inhibited angiogenesis induced by HMGB1 in complex with heparin. HRG inhibited the diffusion of a complex of HMGB1 with heparin from matrigel into surrounding tissue. HRG also competed with HMGB1 for heparin binding in vitro. Moreover, HRG inhibited heparin-dependent vascular endothelial growth factor-A165 (VEGF-A165)-induced angiogenesis. These results strongly suggested that HRG might be an inhibitor of angiogenesis induced by growth factors with heparin binding activity and that HRG may be a potential drug for angiogenic diseases, including tumor growth.
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