title: Perivascular delivery of resolvin D1 inhibits neointimal hyperplasia in a rat model of arterial injury.
abstract: OBJECTIVE
  Lipid mediators derived from omega-3 polyunsaturated fatty acids such as resolvin D1 (RvD1) accelerate the resolution of inflammation and have potential as vascular therapeutics. The objective of this study was to evaluate local perivascular delivery of RvD1 as a means to attenuate neointimal hyperplasia in a rat model of arterial injury.
  
  
  METHODS
  Smooth muscle cells were harvested from rat aortas to study the effects of RvD1 on rat arterial vascular smooth muscle cell responses in vitro, with focus on inflammation, proliferation, migration, cytoskeletal changes, and cytotoxicity. The safety and efficacy of perivascular delivery of RvD1 through thin biodegradable three-layered poly(lactic-co-glycolic acid) wraps or 25% Pluronic F127 gels were studied in a rat model of carotid angioplasty. A total of 200 ng of RvD1 was loaded into each construct for perivascular delivery after injury. Morphometric and histologic analyses were performed 3 and 14 days after injury.
  
  
  RESULTS
  RvD1 attenuated rat arterial vascular smooth muscle cell inflammatory pathways, proliferation, migration, and mitogen-induced cytoskeletal changes in vitro, without evidence of cytotoxicity. RvD1-loaded wraps reduced neointimal formation after carotid angioplasty by 59% vs no-wrap controls (P = .001) and by 45% vs vehicle-wrap controls (P = .002). RvD1-loaded Pluronic gels similarly reduced neointimal formation by 49% vs no-gel controls (P = .02) and by 52% vs vehicle-gel controls (P = .02). No group was associated with infection, thrombosis, or negative vessel remodeling. Wraps were found to be easier to apply than gel constructs. Ki67 proliferation index was significantly lower in RvD1-loaded wrap-treated arteries compared with both no-wrap and vehicle-wrap controls at both 3 and 14 days after injury (65% vs no-wrap group and 70% vs vehicle-wrap group at day 3, 49% vs both control groups at day 14; P < .05). Similarly, oxidative stress (30% and 29%; P < .05) and nuclear factor κB activation (42% and 45%; P < .05) were significantly lower in the RvD1-loaded wrap group compared with both no-wrap and vehicle-wrap controls at 3 days after injury.
  
  
  CONCLUSIONS
  Local perivascular delivery of RvD1 attenuates formation of neointimal hyperplasia without associated toxicity in a rat model of carotid angioplasty. This effect is likely due to attenuation of inflammatory pathways as well as decreased arterial smooth muscle cell proliferation and migration.
authors.affiliation: Department of Surgery and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, Calif.
authors.forename: Bian
authors.initials: B
authors.lastname: Wu
authors.affiliation: Department of Surgery and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, Calif.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Mottola
authors.affiliation: Department of Surgery and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, Calif.
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, Calif.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Lance
authors.affiliation: Department of Surgery and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, Calif.
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, Calif.
authors.forename: Iris O
authors.initials: IO
authors.lastname: Siguenza
authors.affiliation: Department of Surgery and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, Calif.
authors.forename: Tejal A
authors.initials: TA
authors.lastname: Desai
authors.affiliation: Department of Surgery and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, Calif. Electronic address: michael.conte2@ucsf.edu.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Conte
mesh_terms: D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002317:Cardiovascular Agents / Q000008:administration & dosage* / Q000737:chemistry; D002340:Carotid Artery Diseases / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids / Q000008:administration & dosage* / Q000737:chemistry; D004337:Drug Carriers; D004339:Drug Compounding; D006965:Hyperplasia; D018836:Inflammation Mediators / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D019344:Lactic Acid / Q000737:chemistry; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D058426:Neointima; D018384:Oxidative Stress / Q000187:drug effects; D020442:Poloxamer / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D002317:Cardiovascular Agents; D004337:Drug Carriers; D018836:Inflammation Mediators; D019394:Ki-67 Antigen; C498145:Rela protein, rat; D051996:Transcription Factor RelA; C518399:resolvin D1; D020442:Poloxamer; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D004281:Docosahexaenoic Acids; D011100:Polyglycolic Acid; D019344:Lactic Acid