Systemically and topically supplemented leptin fails to reconstitute a normal angiogenic response during skin repair in diabetic ob/ob mice

Aims/hypothesis. In diabetic patients impaired wound healing conditions are a therapeutic problem of clinical importance. Recently, we showed that supplemented leptin induced an acceleration of impaired wound closure in diabetic ob/ob mice by reversion of the delayed re-epithelialization process. Additionally, angiogenesis is central to a normal repair. As leptin has been reported to represent an angiogenic factor, we hypothesized that leptin-mediated angiogenic processes at the wound site might participate in leptin-mediated improvement of disturbed repair in ob/ob mice. Methods. Using a model of excisional wounding, C57BL/6J-ob/ob mice were treated systemically and topically with recombinant murine leptin during the phase of repair. Changes in blood glucose concentrations and body weight were monitored. We measured expression of the vascular endothelial growth factor (VEGF) and the endothelial cell marker protein CD31 as a read-out for angiogenic processes at the wound site. Results. Expression of VEGF protein upon injury was reduced (30 to 40%) in ob/ob mice compared with wild-type C57BL/6 animals. Systemic and topical administration of leptin reconstituted normal wound VEGF expressions but failed to reverse the strongly reduced angiogenic response in ob/ob mice. Immunohistochemistry confirmed that the epithelium and blood vessels located in the granulation tissue expressed the functional leptin receptor obRb isoform during skin repair. Conclusion/Interpretation. These data suggest that leptin reconstituted epithelial expression of VEGF during skin repair in ob/ob mice but failed to improve wound angiogenesis in the granulation tissue. Thus, the accelerated wound closure observed in leptin-supplemented ob/ob mice is not coupled to an improved wound angiogenesis.