Failure of vascular interventions such as angioplasty, stenting, and bypass surgery remains a common clinical problem resulting in considerable morbidity, mortality, and healthcare expenditures. The most common cause of these failures is a narrowing of the vessel lumen (""""""""restenosis"""""""") resulting from excessive thickening of the vessel wall (intimal hyperplasia) and scarring (fibrosis). The response of blood vessels to injury is initiated and potentiated by inflammation. The magnitude of this response, including its temporal and spatial extent, is a primary determinant of the vessel remodeling outcome. Recent studies have suggested that the resolution of inflammation is an active, rather than a passive process, and is mediated by specialized pro-resolving lipid mediators derived from polyunsaturated fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). These mediators - termed lipoxins, resolvins, protectins, and maresins - exert potent effects on inflammatory cells to turn off inflammation and promote a return of homeostasis. Recently we and others have identified direct actions of these pro-resolving mediators on vascular cells which suggest they may be important modulators of vascular healing, and candidate therapeutics for vascular disease. In this translational research proposal, we will examine the hypothesis that restenosis is caused by a relative deficit in resolution following vascular injury. We will examine the molecular mechanisms by which one important class of pro-resolving lipid mediators, the D-series resolvins, exerts anti-inflammatory and cytostatic effects on vascular smooth muscle (VSMC) and adventitial cells. We will characterize the endogenous resolution pathways that are operative in the setting of acute arterial injury using an established animal model, and their manipulation by either dietary or local drug delivery interventions. These studies will yield novel insights into the control of vascular healing, and may lead to new therapeutic approaches leveraging the unique pharmacobiology of pro-resolving lipid mediators in cardiovascular diseases.

Public Health Relevance

Recurrent narrowing of arteries (restenosis) following angioplasty, stenting, or bypass surgery for atherosclerosis is a common problem, which stems from excessive inflammation and scarring of the vessel. We propose that restenosis reflects a relative deficit in the resolution of inflammation, a process which has recently been understood to involve specialized mediators derived from polyunsaturated fatty acids (PUFA), particularly the ?-3 PUFAs present in fish oils. In this research program, we will investigate the mechanisms by which these specialized mediators control vascular healing, and test whether nutritional supplementation or localized delivery of these compounds can reduce vessel scarring after angioplasty and improve function.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
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Charette, Marc F
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Wu, Bian; Werlin, Evan C; Chen, Mian et al. (2018) Perivascular delivery of resolvin D1 inhibits neointimal hyperplasia in a rabbit vein graft model. J Vasc Surg 68:188S-200S.e4
Akagi, Daisuke; Hoshina, Katsuyuki; Watanabe, Toshiaki et al. (2018) Drug Therapy for Abdominal Aortic Aneurysms Utilizing Omega-3 Unsaturated Fatty Acids and Their Derivatives. Curr Drug Targets 19:1309-1317
Conte, Michael S; Desai, Tejal A; Wu, Bian et al. (2018) Pro-resolving lipid mediators in vascular disease. J Clin Invest 128:3727-3735
Schaller, Melinda S; Zahner, Greg J; Gasper, Warren J et al. (2017) Relationship between the omega-3 index and specialized pro-resolving lipid mediators in patients with peripheral arterial disease taking fish oil supplements. J Clin Lipidol 11:1289-1295
Mottola, Giorgio; Chatterjee, Anuran; Wu, Bian et al. (2017) Aspirin-triggered resolvin D1 attenuates PDGF-induced vascular smooth muscle cell migration via the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway. PLoS One 12:e0174936
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
Wu, Bian; Mottola, Giorgio; Chatterjee, Anuran et al. (2017) Perivascular delivery of resolvin D1 inhibits neointimal hyperplasia in a rat model of arterial injury. J Vasc Surg 65:207-217.e3
Wu, Bian; Mottola, Giorgio; Schaller, Melinda et al. (2017) Resolution of vascular injury: Specialized lipid mediators and their evolving therapeutic implications. Mol Aspects Med 58:72-82
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
Pope, Nicolas H; Salmon, Morgan; Davis, John P et al. (2016) D-series resolvins inhibit murine abdominal aortic aneurysm formation and increase M2 macrophage polarization. FASEB J 30:4192-4201

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