Crucial role of CD40 signaling in vascular wall cells in neointimal formation and vascular remodeling after vascular interventions.
Crucial role of CD40 signaling in vascular wall cells in neointimal formation and vascular remodeling after vascular interventions.
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DOI：
10.1161/atvbaha.111.238329
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发表时间：
2012-01
期刊：
影响因子：
--
通讯作者：
Li G
中科院分区：
文献类型：
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作者：
Song Z;Jin R;Yu S;Nanda A;Granger DN;Li G
已表明白细胞中的CD40-TRAF6轴在颈动脉结扎后的新内膜形成中起重要作用。由于 CD40 和 TRAF6 不仅在白细胞中表达，还在血管细胞中表达，因此我们研究了血管壁细胞贡献的 CD40 在致动脉粥样硬化环境中颈动脉结扎后新内膜形成中的作用。在野生型（WT）小鼠中，内侧平滑肌细胞（SMC）中的CD40和TRAF6在损伤后3天和7天时显着上调，但TRAF6上调在CD40−/−小鼠中被消除。在体外，在野生型 SMC 中，细胞因子（TNF-α、IL-1β）通过 NF-κB 依赖性方式诱导 TRAF6 表达，但这种诱导在 CD40 缺陷的 SMC 中被阻断。骨髓嵌合体显示，缺乏血管壁或骨髓相关 CD40 的小鼠的新内膜形成和管腔狭窄显着减少。缺乏血管壁相关的 CD40 会导致单核细胞/巨噬细胞积累、NF-κB 激活和多种促炎介质（ICAM-1、VCAM-1、MCP-1、MMP-9、组织因子）显着减少。体外数据证实，CD40 缺陷或 TRAF6 敲低可通过抑制 NF-κB 激活来抑制 CD40L 诱导的 SMC 促炎表型。此外，体内和体外数据均表明CD40缺陷可阻止损伤诱导的SMC凋亡，但不影响SMC增殖和迁移。血管 SMC 中通过 TRAF6 的 CD40 信号传导似乎以 NF-κB 依赖性方式主要参与新内膜形成。调节局部血管壁上的CD40信号传导可能成为对抗血管再狭窄的新治疗靶点。
It has been shown that CD40-TRAF6 axis in leukocytes plays a significant role in neointimal formation after carotid ligation. Because CD40 and TRAF6 are expressed not only in leukocytes but also in vascular cells, we examined the role of CD40 contributed by vascular wall cells in neointimal formation after carotid ligation in an atherogenic environment. Both CD40 and TRAF6 in medial smooth muscle cells (SMCs) was upregulated significantly at 3 d and more prominently at 7 d after injury in wildtype (WT) mice, but the TRAF6 upregulation was abolished in CD40−/− mice. In vitro, TRAF6 expression was induced by cytokines (TNF-α, IL-1β) via a NF-κB-dependent manner in wildtype SMCs, but this induction was blocked in CD40-deficient SMCs. Bone marrow chimeras revealed a comparable reduction in neointimal formation and lumen stenosis in mice lacking either vascular wall- or bone marrow- associated CD40. Lacking vascular wall-associated CD40 resulted in a significant reduction in monocyte/macrophage accumulation, NF-κB activation, and multiple proinflammatory mediators (ICAM-1, VCAM-1, MCP-1, MMP-9, tissue factor). In vitro data confirmed that CD40 deficiency or TRAF6 knockdown suppressed CD40L-induced proinflammatory phenotype of SMCs by inhibition of NF-κB activation. Moreover, both in vivo and in vitro data showed that CD40 deficiency prevented injury-induced SMC apoptosis, but did not affect SMC proliferation and migration. CD40 signaling through TRAF6 in vascular SMCs seems to be centrally involved in neointimal formation in a NF-κB-dependent manner. Modulating CD40 signaling on local vascular wall may become a new therapeutic target against vascular restenosis.