We thank Germani and Capogrossi (1) for showing interest in our work (5). Previous studies, especially reports by Germani and colleagues (2,–4), document that high-mobility group box-1 (HMGB1) could be involved in the molecular mechanisms that regulate angiogenesis. As reported in our article (5), we started from the previous findings that showed that endogenous HMGB1 is reduced in diabetic skin (6), that HMGB1 stimulates neovascularization in vitro and in vivo normoglycemic models (2,7), and that HMGB1 administration increases levels of several growth factors, including vascular endothelial growth-factor (VEGF) released by cultured cardiac fibroblasts from nondiabetic patients (3).
Given these data and the preexisting evidence, our study's leading objective was to investigate HMGB1's role in ischemia-induced angiogenesis in diabetes. Mice with diabetes have impaired perfusion recovery following femoral artery excision (8). In our study (5), we demonstrated for the first time that disturbed tolerance against severe limb ischemia under hyperglycemia is, at least in part, attributable to the disturbance of the HMGB1 pathway and that the local administration of the HMGB1 protein is sufficient to improve postischemic neoangiogenesis in diabetic mice. There are several mechanisms by which HMGB1 may promote this process (3,9), but we focused our attention on the VEGF pathway, and we showed that this angiogenic response is dependent on VEGF.
Although further investigations are needed, modulation of the HMGB1 system could be a new therapeutic strategy for treating peripheral artery disease in diabetic patients.
No potential conflicts of interest relevant to this article were reported.