Perivascular delivery of resolvin D1 inhibits neointimal hyperplasia in a rabbit vein graft model

Abstract

Objective: Inflammation is a key driver of excessive neointimal hyperplasia within vein grafts. Recent work demonstrates that specialized proresolving lipid mediators biosynthesized from omega-3 polyunsaturated fatty acids, such as resolvin D1 (RvD1), actively orchestrate the process of inflammation resolution. We investigated the effects of local perivascular delivery of RvD1 in a rabbit vein graft model. Methods: Ipsilateral jugular veins were implanted as carotid interposition grafts through an anastomotic cuff technique in New Zealand white rabbits (3–4 kg; N = 80). RvD1 (1 μg) was delivered to the vein bypass grafts in a perivascular fashion, using either 25% Pluronic F127 gel (Sigma-Aldrich, St. Louis, Mo) or a thin bilayered poly(lactic-co-glycolic acid) (PLGA) film. No treatment (bypass only) and vehicle-loaded Pluronic gels or PLGA films served as controls. Delivery of RvD1 to venous tissue was evaluated 3 days later by liquid chromatography-tandem mass spectrometry. Total leukocyte infiltration, macrophage infiltration, and cell proliferation were evaluated by immunohistochemistry. Elastin and trichrome staining was performed on grafts harvested at 28 days after bypass to evaluate neointimal hyperplasia and vein graft remodeling. Results: Perivascular treatments did not influence rates of graft thrombosis (23%), major wound complications (4%), or death (3%). Leukocyte (CD45) and macrophage (RAM11) infiltration was significantly reduced in the RvD1 treatment groups vs controls at 3 days (60%−72% reduction; P < .01). Cellular proliferation (Ki67 index) was also significantly lower in RvD1-treated vs control grafts at 3 days (40%−50% reduction; P < .01). Treatment of vein grafts with RvD1-loaded gels reduced neointimal thickness at 28 days by 61% vs bypass only (P < .001) and by 63% vs vehicle gel (P < .001). RvD1-loaded PLGA films reduced neointimal formation at 28 days by 50% vs bypass only (P < .001). RvD1 treatment was also associated with reduced collagen deposition in vein grafts at 28 days. Conclusions: Local perivascular delivery of RvD1 attenuates vein graft hyperplasia without associated toxicity in a rabbit carotid bypass model. This effect appears to be mediated by both reduced leukocyte recruitment and decreased cell proliferation within the graft. Perivascular PLGA films may also impart protection through biomechanical scaffolding in this venous arterialization model. Our studies provide further support for the potential therapeutic role of specialized proresolving lipid mediators such as D-series resolvins in modulating vascular injury and repair. (J Vasc Surg 2018;■:1–12.) Clinical Relevance: Autologous vein bypass grafts are the most durable means for revascularization in peripheral vascular disease; however, midterm and long-term outcomes are limited by vein graft hyperplasia with associated vein graft failure. Endogenous proresolving lipid mediators such as resolvin D1 have the potential to attenuate vein graft hyperplasia by accelerating repair. This study provides proof of co...

Opposing Effects on Vascular Smooth Muscle Cell Proliferation and Macrophage-induced Inflammation Reveal a Protective Role for the Proresolving Lipid Mediator Receptor ChemR23 in Intimal Hyperplasia

“…Omega-3 fatty acids decrease inflammation ( Serhan, 2014 ), and inhibit intimal hyperplasia in mice ( Li et al, 2015 ). Other studies have shown similar effects after administration of the pro-resolving lipid mediators resolvins and maresins, which are enzymatically formed from omega-3 fatty acids ( Ho et al, 2010 ; Akagi et al, 2015 ; Liu et al, 2018 ; Wu et al, 2018 ). The latter studies provided the initial evidence that stimulating the resolution of inflammation by means of lipid pro-resolving mediators would promote an adequate healing of vascular injury.…”

Pro-resolving lipid mediators in vascular disease

“…Adapted with permission from ref. 48 ship between changes in the O3I and these SPM pathway markers (109). However, downstream bioactive SPMs were sparsely detected in plasma, and measures of endothelial function and systemic inflammation were unchanged following the 1-month intervention.…”

“…Based on the findings from smallanimal models described above, we have sought to develop a platform for pro-resolving vascular therapeutics leveraging polymer and device technologies ( Figure 2). Using poly(lactic-co-glycolic acid) (PLGA) as a biodegradable scaffold, we described thin-film devices capable of directional elution of bioactive RvD1 over several weeks (47,48,96). Others have described similar approaches using biomaterial scaffolds to locally deliver SPMs to subcutaneous tissues (97,98) and bone (99).…”

“…These observations led us to hypothesize that augmentation of resolution via SPMs may mitigate the arterial injury response and reduce restenosis. Efforts in this arena have led to the preclinical development of candidate therapeutic strategies to deliver SPMs locally to arteries and bypass grafts, described in further detail below (45)(46)(47)(48).…”

Vascular science: A glimpse into the future

“…Weber et al 17 report a new bacterial nanocellulose-derived vascular graft in a sheep model, another step toward developing better grafts. Wu et al 18 show that resolvin D1 promotes resolution of inflammation and inhibits neointimal hyperplasia. And, Braetz et al 19 show that sphingosine-1-phosphate receptor-1 regulates neointimal hyperplasia and may be another good pharmacological target.…”