Reprogramming Macrophages to Improve Vascular Healing in Diabetes

Providence Va Medical Center, Providence RI

Investigators

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Abstract

Impaired wound healing in US 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 early inflammatory macrophage VEGF-A production in promoting consequent angiogenesis/ arteriogenesis required for adequate wound healing. We determined macrophage proangiogenic VEGF-A isoform transcription to be dependent on autocrine IL-1β-IL-1R signaling through activation of nuclear NF-κB and binding of NF-κB to the VEGF-A promoter region. Analogous to macrophage IL-1β-deleted mice, mice with experimental diabetes demonstrated impaired tissue proangiogenic VEGF-A expression and consequent reductions in wound healing and arteriogenesis. Under inflammatory conditions, bone marrow derived macrophages (BMDMs) from diabetic mice expressed reduced VEGF-A consistent with reduced signaling response to IL-1β, and interestingly, there is reduced expression of several key IL-1R signaling complex components, suggesting an impaired responsiveness to IL-1β. Our working model is that DM uncouples IL-1R signaling from VEGF-A transcription, causing impaired proangiogenic VEGF-A expression and consequent decreased angiogenesis-based healing. In this VA Research Supplement to Promote Diversity proposal, we seek to reactivate macrophage VEGF-A expression by effectively bypassing IL-1R signaling and upregulating NF-κB activity directly. The primary hypothesis is that rescue of DM-mediated impairments in VEGF-A-dependent angiogenesis via direct upregulation of NF-κB activity is a viable therapeutic angiogenesis strategy for wound healing. We aim to 1) demonstrate that myeloid expression of constitutively active IKK-2 can rescue proangiogenic VEGF-A expression and VEGF-A-dependent angiogenesis in the context of macrophage IL-1R-deletion; and 2) demonstrate that BMDMs programed to express constitutively active IKK-2 are sufficient to increase wound healing angiogenesis and arteriogenesis using mice with experimental DM. By manipulating mechanistic pathways downstream of IL-1R signaling-dependent VEGF-A expression to therapeutically reactivate diabetic macrophage angiogenic and wound healing responses, we will validate a therapeutic angiogenesis strategy that has tremendous potential to impact the lives of US veterans and all Americans. Moreover, this proposal serves as a robust training platform for Dr. Roberto Mendez, a Mexican American and US veteran, who is committed to developing a VA-based research career focused on veteran health. These studies will provide him with important preliminary data to support his own VA CDA-1 application proposal within the next two years.