Resolvin E1 attenuates inj ury‐induced vascular neointimal formation by inhibition of inflammatory responses and vascular smooth muscle cell migration

Abstract

Mechanical insults, such as stent implantation, can induce endothelial injury, vascular inflammation, and ultimately lead to vascular neointimal hyperplasia. Resolvin E1 (RvE1), derived from the ω3 fatty acid eicosapentaenoic acid, can facilitate the resolution of inflammation in many settings. We therefore aimed to determine if there was a role for RvE1 in preventing neointimal formation after arterial injury and to understand the underlying mechanisms. Vascular inflammation and neointimal hyperplasia were induced by wire injury in the femoral arteries of mice. Administration of exogenous RvE1 and endogenously generated RvE1 via dietary supplementation with eicosapentaenoic acid and aspirin markedly reduced vascular neointima formation in this model. Mechanistically, RvE1 was found to inhibit vascular neutrophil infiltration, promote macrophage polarization toward an M2-like phenotype, suppress T-cell trafficking by reducing RANTES secretion from vascular smooth muscle cells, and inhibit vascular smooth muscle cell migration. In summary, RvE1 demonstrated a protective role against vascular inflammation and remodeling in response to mechanical injury, suggesting that it may serve as an adjuvant therapeutic agent for percutaneous coronary interventions, such as stent implantation.-Liu, G., Gong, Y., Zhang, R., Piao, L., Li, X., Liu, Q., Yan, S., Shen, Y., Guo, S., Zhu, M., Yin, H., Funk, C. D., Zhang, J., Yu, Y. Resolvin E1 attenuates injury-induced vascular neointimal formation by inhibition of inflammatory responses and vascular smooth muscle cell migration.

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.…”

Lipoxin and Resolvin Receptors Transducing the Resolution of Inflammation in Cardiovascular Disease

“…Importantly, lipoxins are produced during percutaneous coronary interventions (PCI) and the administration of proresolving lipid mediators reduces intimal hyperplasia in different murine models of vascular injury ( Miyahara et al, 2013 ; Akagi et al, 2015 ; Petri et al, 2015b ; Liu et al, 2018a ). The protective effect of ATL on intimal hyperplasia is however not observed in ALX/FPR2 knock-out mice ( Petri et al, 2015b ).…”

“…Exogenous administration of RvE1 reduces atherosclerosis ( Hasturk et al, 2015 ; Salic et al, 2016 ) and intimal hyperplasia ( Liu et al, 2018a ) in different animal models, hence raising the notion of beneficial cardiovascular effects being transduced trough ERV1/ChemR23. This was recently determined by the generation of hyperlipidemic ApoE −/− mice lacking ERV1/ChemR23, which exhibit exacerbated atherosclerosis with larger lesions containing more macrophages compared with ERV1/ChemR23 expressing ApoE −/− littermates ( Laguna-Fernandez et al, 2018 ).…”

2,3,7,8‐Tetrachlorodibenzo‐p‐dioxin promotes injury‐induced vascular neointima formation in mice

“…Intimal area and medial area were measured using Image J software (National Institutes of Health, Bethesda, MD, USA). The intima to media (I/M) ratio and arterial narrowness (%) were calculated routinely as previous reported by Liu et al (21).…”

“…The sections or coverslips were then blocked in 3% bovine serum albumin in PBS/Triton (0.3% Triton X-100 in PBS) at room temperature for 60 min and incubated with the following primary antibodies: anti-CD68 (1:200; MilliporeSigma); anti-CD11b (1:100; BD Biosciences); anti-Kiel clone 67 (Ki67, 1:200; Abcam, Cambridge, MA, USA); anti-a smooth muscle actin (a-SMA) (1:1000; MilliporeSigma) and anti-c-Jun (1:500; Abcam) at 4°C overnight. The inflammation was detected by using CD68 and CD11b antibody (21). The slides were then washed with PBS for 3 times and incubated with secondary antibodies for 2 h at room temperature, counterstained with DAPI, sealed with antifade reagent (Thermo Fisher Scientific).…”