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Perivascular mast cells regulate vein graft neointimal formation and remodeling.

ABSTRACT: Objective. Emerging evidence suggests an important role for mast cells in vein graft failure. This study addressed the hypothesis that perivascular mast cells regulate in situ vascular inflammatory and proliferative responses and subsequent vein graft neointimal lesion formation, using an optimized local mast cell reconstitution method. Methods and Results. Neointimal hyperplasia was induced by insertion of a vein graft into the right carotid artery in wild type and mast cell deficient Kit(W-sh/W-sh) mice. In some experiments, mast cells were reconstituted systemically (tail vein injection of bone marrow-derived mast cells) or locally (directly into the right neck area) prior to vein grafting. Vein graft neointimal lesion formation was significantly (P < 0.05) reduced in Kit(W-sh/W-sh) mice. Mast cell deficiency reduced the number of proliferating cells, and inhibited L-selectin, CCL2, M-CSF and MIP-3? expression in the vein grafts. Local but not systemic mast cell reconstitution restored a perivascular mast cell population that subsequently promoted neointimal formation in mast cell deficient mice. Conclusion. Our data demonstrate that perivascular mast cells play a key role in promoting neointima formation by inducing local acute inflammatory and proliferative responses. These results suggest that ex vivo intraoperative targeting of mast cells may have therapeutic potential for the prevention of pathological vein graft remodeling.

SUBMITTER: Wu J

PROVIDER: S-EPMC4548472 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Perivascular mast cells regulate vein graft neointimal formation and remodeling.

Wu Junxi J Grassia Gianluca G Cambrook Helen H Ialenti Armando A MacRitchie Neil N Carberry Jaclyn J Wadsworth Roger M RM Lawrence Catherine C Kennedy Simon S Maffia Pasquale P

PeerJ 20150818

Objective. Emerging evidence suggests an important role for mast cells in vein graft failure. This study addressed the hypothesis that perivascular mast cells regulate in situ vascular inflammatory and proliferative responses and subsequent vein graft neointimal lesion formation, using an optimized local mast cell reconstitution method. Methods and Results. Neointimal hyperplasia was induced by insertion of a vein graft into the right carotid artery in wild type and mast cell deficient Kit(W-sh/ ...[more]

PMID: 26312183

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Project description:ObjectiveInflammation 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.MethodsIpsilateral 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.ResultsPerivascular 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.ConclusionsLocal 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.

Project description:Innate immunity drives numerous cardiovascular pathologies. Vein bypass grafting procedures are frequently accompanied by low-grade wound contamination. We hypothesized that a peri-graft innate immune challenge, via an outside-in route, augments inflammatory responses, which subsequently drive a component of negative vein graft wall adaptations; moreover, adipose tissue mediates this immune response.The inferior vena cava from a donor mouse was implanted into the common carotid artery of a recipient mouse utilizing a validated cuff technique (9-week-old male C57BL/6J mice). Slow-release low-dose (5 ?g) lipopolysaccharide (LPS) (n = 9) or vehicle (n = 9) was applied peri-graft; morphologic analysis was completed (day 28). In parallel, vein-grafted mice received peri-graft LPS (n = 12), distant subcutaneous LPS (n = 6), or vehicle (n = 12), then day-1 and -3 harvest of grafts and adipose tissue for cytokines and toll-like receptor (TLR) signaling mRNA expression (qRT-PCR).All recipient mice survived, and all vein grafts were patent. Acute low-dose local LPS challenge enhanced vein graft lumen loss (P = .04) and tended to augment intimal hyperplasia (P = .06). The surgical trauma of vein grafting universally upregulated key pro- and anti-inflammatory mediators within the day-1 graft wall, but varied on TLR signaling gene expression. Local and distant LPS accentuated these patterns until at least postoperative day 3. LPS challenge enhanced the inflammatory response in adipose tissue (locally > distantly); local LPS upregulated adipose TLR-4 dramatically.Perivascular and distant inflammatory challenges potentiate the magnitude and duration of inflammatory responses in the early vein graft wall, negatively modulating wall adaptations, and thus, potentially contribute to vein graft failure. Furthermore, surgery activates innate immunity in adipose tissue, which is augmented (regionally > systemically) by LPS. Modulation of these local and distant inflammatory signaling networks stands as a potential strategy to enhance the durability of vascular interventions such as vein grafts.

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Perivascular mast cells regulate vein graft neointimal formation and remodeling.

Publications

Perivascular mast cells regulate vein graft neointimal formation and remodeling.

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