title: Systemic delivery of proresolving lipid mediators resolvin D2 and maresin 1 attenuates intimal hyperplasia in mice.
abstract: Vascular injury induces a potent inflammatory response that influences vessel remodeling and patency, limiting long-term benefits of cardiovascular interventions such as angioplasty. Specialized proresolving lipid mediators (SPMs) derived from ω-3 polyunsaturated fatty acids [eicosapentaenoic acid and docosahexaenoic acid (DHA)] orchestrate resolution in diverse settings of acute inflammation. We hypothesized that systemic administration of DHA-derived SPMs [resolvin D2 (RvD2) and maresin 1 (MaR1)] would influence vessel remodeling in a mouse model of arterial neointima formation (carotid ligation). In vitro, SPM treatment inhibited mouse aortic smooth muscle cell migration (IC₅₀ ≅ 1 nM) to a PDGF gradient and reduced TNF-α-stimulated p65 translocation, superoxide production, and proinflammatory gene expression (MCP-1). In vivo, adult FVB mice underwent unilateral carotid artery ligation with administration of RvD2, MaR1, or vehicle (100 ng by intraperitoneal injection at 0, 1, 3, 5, and 7 d after ligation). In ligated carotid arteries at 4 d, SPM treatment was associated with reduced cell proliferation and neutrophil and macrophage recruitment and increased polarization of M2 macrophages in the arterial wall. Neointimal hyperplasia (at 14 d) was notably attenuated in RvD2 (62%)- and MaR1 (67%)-treated mice, respectively. Modulation of resolution pathways may offer new opportunities to regulate the vascular injury response and promote vascular homeostasis.
authors.affiliation: Department of Surgery and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Akagi
authors.affiliation: Department of Surgery and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Mian
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Surgery and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Toy
authors.affiliation: Department of Surgery and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Anuran
authors.initials: A
authors.lastname: Chatterjee
authors.affiliation: Department of Surgery and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA michael.conte2@ucsf.edu.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Conte
mesh_terms: D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics; D004281:Docosahexaenoic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006965:Hyperplasia / Q000517:prevention & control; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D058426:Neointima / Q000473:pathology / Q000517:prevention & control*; D020556:Neutrophil Infiltration / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013481:Superoxides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D017539:Tunica Intima / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D066253:Vascular Remodeling / Q000187:drug effects
chemical_list: C535211:7,14-dihydroxydocosa-4,8,10,12,16,19-hexaenoic acid; D016207:Cytokines; D019394:Ki-67 Antigen; D014409:Tumor Necrosis Factor-alpha; C545423:resolvin D2; D013481:Superoxides; D004281:Docosahexaenoic Acids
keywords: fatty acid; inflammation; neointimal hyperplasia; vascular remodeling