Aspirin-triggered 15-epi-lipoxin A4 signals through FPR2/ALX in vascular smooth muscle cells and protects against intimal hyperplasia after carotid ligation

Petri, Marcelo H.; Laguna-Fernández, Andrés; Tseng, Chi-Nan; Hedin, Ulf; Perretti, Mauro; Bäck, Magnus

doi:10.1016/j.ijcard.2014.11.010

Cited by 51 publications

(49 citation statements)

References 10 publications

(18 reference statements)

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“…Signaling through these receptors in SMC induces opposite effects in vivo and in vitro; the LTB 4 -BLT 1 pathway stimulates SMC migration and proliferation, whereas LXA 4 reduces these SMC responses by means of FPR2/ALX [6]. Similar opposing effects of BLT 1 and FPR2/ALX have also been reported in macrophages.…”

Section: Introductionmentioning

confidence: 65%

Differential regulation of monocytic expression of leukotriene and lipoxin receptors

Petri

Thul

Ovchinnikova

et al. 2015

Prostaglandins & Other Lipid Mediators

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Section: Introductionmentioning

confidence: 65%

Differential regulation of monocytic expression of leukotriene and lipoxin receptors

Petri

Thul

Ovchinnikova

et al. 2015

Prostaglandins & Other Lipid Mediators

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“…However, a recent study indicates that mice lacking FPR2 and FPR3 are partially protected from atherosclerosis at a later stage. 27 Thus, subsequent studies are required to define the role of AnxA1 and its therapeutic potential during atheroprogression and plaque destabilization clearly.…”

Section: Apoe -/-+ αCxcr2mentioning

confidence: 99%

Annexin A1 Counteracts Chemokine-Induced Arterial Myeloid Cell Recruitment

Drechsler¹,

Jong²,

Rossaint³

et al. 2015

Circulation Research

128

123

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Rationale: Chemokine-controlled arterial leukocyte recruitment is a crucial process in atherosclerosis. Formyl peptide receptor 2 (FPR2) is a chemoattractant receptor that recognizes proinflammatory and proresolving ligands. The contribution of FPR2 and its proresolving ligand annexin A1 to atherosclerotic lesion formation is largely undefined. Objective: Because of the ambivalence of FPR2 ligands, we here investigate the role of FPR2 and its resolving ligand annexin A1 in atherogenesis. Methods and Results: Deletion of FPR2 or its ligand annexin A1 enhances atherosclerotic lesion formation, arterial myeloid cell adhesion, and recruitment. Mechanistically, we identify annexin A1 as an endogenous inhibitor of integrin activation evoked by the chemokines CCL5, CCL2, and CXCL1. Specifically, the annexin A1 fragment Ac2-26 counteracts conformational activation and clustering of integrins on myeloid cells evoked by CCL5, CCL2, and CXCL1 through inhibiting activation of the small GTPase Rap1. In vivo administration of Ac2-26 largely diminishes arterial recruitment of myeloid cells in a FPR2-dependent fashion. This effect is also observed in the presence of selective antagonists to CCR5, CCR2, or CXCR2, whereas Ac2-26 was without effect when all 3 chemokine receptors were antagonized simultaneously. Finally, repeated treatment with Ac2-26 reduces atherosclerotic lesion sizes and lesional macrophage accumulation. Conclusions: Instructing the annexin A1-FPR2 axis harbors a novel approach to target arterial leukocyte recruitment. With the ability of Ac2-26 to counteract integrin activation exerted by various chemokines, delivery of Ac2-26 may be superior in inhibition of arterial leukocyte recruitment when compared with blocking individual chemokine receptors.

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“…18–20,31 Attenuation of growth factor-stimulated VSMC migration by SPMs has been observed in vitro. 17,19–21,31 RvD1 exposure induces cytoskel etal changes in VSMCs corresponding to an antimigratory phenotype, 17,19,31 probably through the cyclic adenosine monophosphate-protein kinase A pathway. 38 Furthermore, SPMs have shown modest antiproliferative effects on VSMCs both in vitro 19–21,31 and in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…19–21,31 The role of inflammation in vein graft disease has been well described. 8,9,39 Trauma during vein harvest and hemodynamic stresses associated with arterialization lead to activation of inflammatory pathways, local expression of cytokines, and infiltration of neutrophils and monocytes.…”

Section: Discussionmentioning

confidence: 99%

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

Werlin

Chen

et al. 2018

Journal of Vascular Surgery

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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...

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Aspirin-triggered 15-epi-lipoxin A4 signals through FPR2/ALX in vascular smooth muscle cells and protects against intimal hyperplasia after carotid ligation

Cited by 51 publications

References 10 publications

Differential regulation of monocytic expression of leukotriene and lipoxin receptors

Differential regulation of monocytic expression of leukotriene and lipoxin receptors

Annexin A1 Counteracts Chemokine-Induced Arterial Myeloid Cell Recruitment

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

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