Perivascular delivery of resolvin D1 inhibits neointimal hyperplasia in a rat model of arterial injury

Abstract

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. Smooth muscle cells were harvested from rat aortas to study the effects of RvD1 on rat arterial vascular smoothmuscle cell responses invitro, 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. Atotal of 200ng of RvD1 was loaded into each construct for perivascular delivery after injury. Morphometric and histologic analyses were performed 3 and 14days after injury. RvD1 attenuated rat arterial vascular smooth muscle cell inflammatory pathways, proliferation, migration, and mitogen-induced cytoskeletal changes invitro, 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 14days 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 3days after injury. 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.