Monocyte chemoattractant protein-1/CCR2 axis promotes vein graft neointimal hyperplasia through its signaling in graft-extrinsic cell populations.
Monocyte chemoattractant protein-1/CCR2 axis promotes vein graft neointimal hyperplasia through its signaling in graft-extrinsic cell populations.
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DOI：
10.1161/atvbaha.112.255786
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发表时间：
2012-10
期刊：
影响因子：
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通讯作者：
Jiang Z
中科院分区：
文献类型：
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作者：
Fu C;Yu P;Tao M;Gupta T;Moldawer LL;Berceli SA;Jiang Z
评估直接和间接MCP-1/CCR2信号传导，并鉴定在静脉移植物（VG）新生内膜增生（NIH）发展过程中MCP-1的细胞产生者和效应者。基因组分析显示，与CCR2KO VGs相比，WT VGs中有13种炎症途径的过度表达。进一步的研究使用MCP-1和CCR2缺陷小鼠的各种vg -宿主组合来修饰静脉壁内（移植物内源组）和静脉壁外（移植物外源组）细胞的基因型。CCR2缺陷仅在移植物壁外源细胞中才抑制NIH， MCP-1缺陷需要其在移植物壁内源和外源细胞中都有效才能抑制NIH。删除MCP-1或CCR2对抑制NIH同样有效。主要新生内膜细胞群中CCR2缺乏对NIH没有影响。MCP-1直接刺激原代新生内膜SMCs对细胞增殖和基质转换的影响最小，证实了其间接作用机制。MCP-1/CCR2轴通过其在移植物外源性细胞中的信号传导加速NIH，特别是循环炎症细胞，移植物壁的内源性和外源性细胞都是关键的MCP-1产生者。这些发现强调了全身抗MCP-1/CCR2治疗的重要性。
To evaluate direct versus indirect MCP-1/CCR2 signaling and identify the cellular producers and effectors for MCP-1 during neointimal hyperplasia (NIH) development in vein grafts (VG). Genomic analysis revealed an over-representation of 13 inflammatory pathways in WT VGs compared to CCR2KO VGs. Further investigation with various VG-host combinations of MCP-1 and CCR2 deficient mice were used to modify the genotype of cells both inside (graft intrinsic group) and outside of the vein wall (graft extrinsic group). CCR2 deficiency inhibited NIH only when present in cells extrinsic to the graft wall, MCP-1 deficiency required its effectiveness in cells both intrinsic and extrinsic to the graft wall to suppress NIH. Deletion of either MCP-1 or CCR2 was equally effective in inhibiting NIH. CCR2 deficiency in the predominant neointimal cell population had no impact on NIH. Direct MCP-1 stimulation of primary neointimal SMCs had minimal influence on cell proliferation and matrix turnover, confirming an indirect mechanism of action. MCP-1/CCR2 axis accelerates NIH via its signaling in graft extrinsic cells, particularly circulating inflammatory cells, with cells both intrinsic and extrinsic to the graft wall being critical MCP-1 producers. These findings underscore the importance of systemic treatment for anti MCP-1/CCR2 therapies.