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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL106173-08
Application #
9395928
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Reid, Diane M
Project Start
2011-08-01
Project End
2020-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
8
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Cai, Bishuang; Thorp, Edward B; Doran, Amanda C et al. (2017) MerTK receptor cleavage promotes plaque necrosis and defective resolution in atherosclerosis. J Clin Invest 127:564-568
Chatterjee, Anuran; Komshian, Sevan; Sansbury, Brian E et al. (2017) Biosynthesis of proresolving lipid mediators by vascular cells and tissues. FASEB J 31:3393-3402
Fredman, Gabrielle; Spite, Matthew (2017) Specialized pro-resolving mediators in cardiovascular diseases. Mol Aspects Med 58:65-71
Lance, Kevin D; Chatterjee, Anuran; Wu, Bian et al. (2017) Unidirectional and sustained delivery of the proresolving lipid mediator resolvin D1 from a biodegradable thin film device. J Biomed Mater Res A 105:31-41
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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