High mobility group box 1 complexed with heparin induced angiogenesis in a matrigel plug assay

Angiogenesis involves complex processes mediated by several factors and is associated with inflammation and wound healing. High mobility group box 1 (HMGB1) is released from necrotic cells as well as macrophages and plays proinflammatory roles. In the present study, we examined whether HMGB1 would exhibit angiogenic activity in a matrigel plug assay in mice. HMGB1 in combination with heparin strongly induced angiogenesis, whereas neither HMGB1 nor heparin alone showed such angiogenic activity. The heparin-dependent induction of angiogenesis by HMGB1 was accompanied by increases in the expression of tumor necrosis factor-α (TNF-α) and vascular endothelial growth factor-A₁₂₀ (VEGF-A₁₂₀). It is likely that the dependence of the angiogenic activity of HMGB1 on heparin was due to the efficiency of the diffusion of the HMGBl-heparin complex from matrigel to the surrounding areas. VEGF-A₁₆₅ possessing a heparin-binding domain showed a pattern of heparin-dependent angiogenic activity similar to that of HMGB1. The presence of heparin also inhibited the degradation of HMGB1 by plasmin in wtro. Taken together, these results suggested that HMGB1 in complex with heparin possesses remarkable angiogenic activity, probably through the induction of TNF-α and VEGF-A₁₂₀.