Reprogramming Macrophages to Improve Vascular Healing in Diabetes

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Impaired wound healing in U.S. veterans with diabetes mellitus is a major source of morbidity and mortality as well as a large financial strain on the VA health care system. Current treatment paradigms, including debridement of necrotic tissue, infection control, local ulcer care, mechanical off-loading, and management of blood glucose levels, are modestly effective at best. Despite much research in this area, the critical molecular mechanisms regulating angiogenesis-directed wound healing remain minimally defined. Recently, our group identified an important role for inflammatory macrophage VEGF-A production in consequent angiogenesis/ arteriogenesis required for adequate wound healing. Preliminary data support that VEGF-A expression is increased in “classic inflammatory” macrophages relative to “alternatively activated” or wound healing macrophages. Our preliminary data also identified that macrophage proangiogenic VEGF-A isoform expression is dependent on expression of the potent inflammatory cytokine, IL-1β. Animals with macrophage deletion of IL-1β demonstrated severely impaired macrophage VEGF-A expression and consequent decreases in angiogenesis and arteriogenesis. We have begun to define a mechanistic pathway, whereby autocrine IL-1β- IL-1R signaling promotes transcription of proangiogenic VEGF-A, in part, through activation of NF-kB and STAT3 downstream of the IL-1R. We seek to understand the impact of diabetes on this macrophage proangiogenic mechanism. Mice with experimental diabetes have profound delays in wound healing in a full thickness dermal punch biopsy model and perfusion recovery in a hind limb ischemia model of femoral artery ligation. Isolated macrophages from these diabetic mice demonstrated reduced inflammatory response to IL-1β via reduced expression of IL-1R signaling complex components along with consequent reductions in VEGF-A expression, consistent with the macrophage IL-1β-deletion model. The primary hypothesis is that diabetes mellitus results in reduced macrophage IL-1β-dependent VEGF-A expression with consequent impairment in angiogenesis-dependent wound healing, consistent with the macrophage IL-1β-deletion model. We seek to 1) demonstrate disrupted macrophage IL-1β signaling-dependent proangiogenic VEGF-A isoform expression to be a major mechanism of impaired angiogenesis and wound healing in DM; and 2) validate defective monocyte/macrophage IL-1R signaling-dependent VEGF-A expression from patients with DM who develop chronic lower extremity ulcers despite usual standard of care. By defining inflammatory macrophages as key, early drivers of angiogenesis required for adequate wound healing, our proposed studies support a paradigm shift away from an anti-inflammatory macrophage strategy being required to activate wound healing, allowing for macrophage reprograming strategies that promote appropriate activation of inflammatory macrophages toward consequent angiogenesis-dependent wound healing.