Department of Neurosurgery, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130, USA.
Arterioscler Thromb Vasc Biol. 2012 Jan;32(1):50-64. doi: 10.1161/ATVBAHA.111.238329. Epub 2011 Oct 13.
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 days and more prominently at 7 days after injury in wildtype mice, but the TRAF6 upregulation was abolished in CD40(-/-) mice. In vitro, TRAF6 expression was induced by cytokines (tumor necrosis factor -α, interleukin-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.
已经证明白细胞中的 CD40-TRAF6 轴在颈动脉结扎后内膜新生中起着重要作用。由于 CD40 和 TRAF6 不仅在白细胞中表达，而且在血管细胞中表达，我们研究了在动脉粥样硬化环境中颈动脉结扎后血管壁细胞 CD40 对内膜新生形成的作用。
在野生型小鼠中，损伤后 3 天和 7 天，中膜平滑肌细胞（SMCs）中的 CD40 和 TRAF6 显著上调，而在 CD40（-/-）小鼠中 TRAF6 的上调被消除。在体外，细胞因子（肿瘤坏死因子-α、白细胞介素-1β）通过 NF-κB 依赖性途径诱导 TRAF6 在野生型 SMC 中表达，但在 CD40 缺陷型 SMC 中这种诱导被阻断。骨髓嵌合体显示，缺乏血管壁或骨髓相关 CD40 的小鼠中，内膜新生和管腔狭窄的程度相当减少。缺乏血管壁相关 CD40 导致单核细胞/巨噬细胞积聚、NF-κB 激活和多种促炎介质（ICAM-1、VCAM-1、MCP-1、MMP-9、组织因子）显著减少。体外数据证实，CD40 缺陷或 TRAF6 敲低通过抑制 NF-κB 激活抑制 CD40L 诱导的 SMC 促炎表型。此外，体内和体外数据均表明，CD40 缺陷可防止损伤诱导的 SMC 凋亡，但不影响 SMC 增殖和迁移。
血管 SMC 中的 CD40 信号通过 TRAF6 似乎以 NF-κB 依赖的方式参与内膜新生。调节局部血管壁的 CD40 信号可能成为对抗血管再狭窄的新治疗靶点。
