Impaired tissue vascularization is a critical feature of peripheral artery disease (PAD) and diabetes and can lead to tissue necrosis and amputation. Several clinical strategies have been designed to increase revascularization in PAD patients beyond the current standard of care (e.g., endovascular procedures and bypass grafting), including delivery of growth factors and cell-based therapies. While variably successful, these therapies have limited efficacy in part because they do not address the underlying chronic inflammation, which is a primary feature of PAD and diabetes. Tissue revascularization is a critical component of normal wound- healing and is regulated in part by macrophages. Resolvins are a new family of lipid mediators biosynthesized during the resolution phase of inflammation by macrophages. Resolvins limit inflammatory signaling and neutrophil chemotaxis, while simultaneously promoting the clearance of apoptotic cells by macrophages. In this funding period, we found that diabetes impairs resolution and that resolvins restore defective resolution and promote cutaneous wound healing in diabetes. Our recent results indicate that resolvins promote ischemic revascularization, suggesting that they have new roles in activating the wound-healing program. This renewal is designed to test the innovative hypothesis that resolvins generated by macrophages promote revascularization during hind limb ischemia (HLI). This hypothesis postulates that by resolving inflammation, resolvins can also rescue defective revascularization in atherosclerosis and diabetes.
Specific aims of this application are: 1. Determine the biosynthesis and endogenous roles of resolvins in revascularization during HLI. We identified resolvin D1 (RvD1) and RvD2 in both skeletal muscle and bone marrow during HLI. Here, we will determine how their production relates to inflammation-resolution and revascularization, determine how resolvin production is affected by adoptive transfer of monocytes, and how genetic deficiency of recently identified RvD1 and RvD2 receptors impacts revascularization; 2. Delineate the mechanisms whereby resolvins enhance ischemic revascularization. We found that resolvins enhance limb perfusion during HLI by promoting arteriogenesis. In this aim, we will determine whether their actions in promoting arteriogenesis are affected by genetic deficiency of resolvin receptors in myeloid cells or endothelial cells and determine how resolvins regulate arteriogenic phenotypes of macrophages and endothelial cells; and 3. Assess whether resolvins promote revascularization in mice with pre-existing atherosclerosis or diabetes. We will determine how these chronic inflammatory diseases impact resolvin biosynthesis and eicosanoid tissue profiles and whether resolvins enhance revascularization while resolving inflammation. Completion of these aims will provide entirely new information about the biological functions of resolvins that could potentially lead to the development of a new class of therapeutics that both resolve inflammation and increase tissue perfusion.
This project will provide a new understanding about the role of inflammation-resolving lipid mediators in tissue revascularization during ischemia. Importantly, the results of these studies could inform the development of new treatments for promoting tissue revascularization and resolving inflammation in patients with peripheral atherosclerosis and critical limb ischemia.
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|Colby, Jennifer K; Abdulnour, Raja-Elie E; Sham, Ho Pan et al. (2016) Resolvin D3 and Aspirin-Triggered Resolvin D3 Are Protective for Injured Epithelia. Am J Pathol 186:1801-1813|
|Fredman, Gabrielle; Hellmann, Jason; Proto, Jonathan D et al. (2016) An imbalance between specialized pro-resolving lipid mediators and pro-inflammatory leukotrienes promotes instability of atherosclerotic plaques. Nat Commun 7:12859|
|Zhang, Michael J; Sansbury, Brian E; Hellmann, Jason et al. (2016) Resolvin D2 Enhances Postischemic Revascularization While Resolving Inflammation. Circulation 134:666-680|
|Hellmann, Jason; Sansbury, Brian E; Holden, Candice R et al. (2016) CCR7 Maintains Nonresolving Lymph Node and Adipose Inflammation in Obesity. Diabetes 65:2268-81|
|Cai, Bishuang; Thorp, Edward B; Doran, Amanda C et al. (2016) MerTK cleavage limits proresolving mediator biosynthesis and exacerbates tissue inflammation. Proc Natl Acad Sci U S A 113:6526-31|
|Sansbury, Brian E; Spite, Matthew (2016) Resolution of Acute Inflammation and the Role of Resolvins in Immunity, Thrombosis, and Vascular Biology. Circ Res 119:113-30|
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