Diabetic foot disease is a major health problem, which affects 15% of the 200 million patients with diabetes worldwide. Diminished peripheral blood flow and decreased local neovascularization are critical factors that contribute to the delayed or nonhealing
wounds in these patients. The correction of impaired local angiogenesis may be a key component in developing therapeutic protocols for treating chronic
wounds of the lower extremity and
diabetic foot ulcers. Endothelial progenitor cells (EPCs) are the key cellular effectors of postnatal neovascularization and play a central role in wound healing, but their circulating and
wound-level numbers are decreased in diabetes, implicating an abnormality in
EPC mobilization and homing mechanisms. The deficiency in
EPC mobilization is presumably due to impairment of eNOS-NO cascade in bone marrow (BM).
Hyperoxia, induced by a clinically relevant
hyperbaric oxygen therapy (HBO) protocol, can significantly enhance the mobilization of EPCs from the BM into peripheral blood. However, increased circulating EPCs failed to reach to
wound tissues. This is partly a result of downregulated production of
SDF-1alpha in local
wound lesions with diabetes. Administration of exogenous
SDF-1alpha into
wounds reversed the
EPC homing impairment and, with
hyperoxia, synergistically enhanced
EPC mobilization, homing, neovascularization, and wound healing.