Institute of Molecular Cardiovascular Research, RWTH Aachen University, Aachen, Germany.
Circulation. 2010 Sep 7;122(10):1026-36. doi: 10.1161/CIRCULATIONAHA.110.954370. Epub 2010 Aug 23.
Receptor binding of complement C5a leads to proinflammatory activation of many cell types, but the role of receptor-mediated action during arterial remodeling after injury has not been studied. In the present study, we examined the contribution of the C5a receptor (C5aR) to neointima formation in apolipoprotein E-deficient mice employing a C5aR antagonist (C5aRA) and a C5aR-blocking monoclonal antibody.
Mice fed an atherogenic diet were subjected to wire-induced endothelial denudation of the carotid artery and treated with C5aRA and anti-C5aR-blocking monoclonal antibody or vehicle control. Compared with controls, neointima formation was significantly reduced in mice receiving C5aRA or anti-C5aR-blocking monoclonal antibody for 1 week but not for 3 weeks, attributable to an increased content of vascular smooth muscle cells, whereas a marked decrease in monocyte and neutrophil content was associated with reduced vascular cell adhesion molecule-1. As assessed by immunohistochemistry, reverse transcription polymerase chain reaction, and flow cytometry, C5aR was expressed in lesional and cultured vascular smooth muscle cells, upregulated by injury or tumor necrosis factor-alpha, and reduced by C5aRA. Plasma levels and neointimal plasminogen activator inhibitor-1 peaked 1 week after injury and were downregulated in C5aRA-treated mice. In vitro, C5a induced plasminogen activator inhibitor-1 expression in endothelial cells and vascular smooth muscle cells in a C5aRA-dependent manner, possibly accounting for higher vascular smooth muscle cell immigration.
One-week treatment with C5aRA or anti-C5aR-blocking monoclonal antibody limited neointimal hyperplasia and inflammatory cell content and was associated with reduced vascular cell adhesion molecule-1 expression. However, treatment for 3 weeks failed to reduce but rather stabilized plaques, likely by reducing vascular plasminogen activator inhibitor-1 and increasing vascular smooth muscle cell migration.
补体 C5a 受体的结合导致许多细胞类型的促炎激活，但在损伤后动脉重塑过程中受体介导的作用的作用尚未研究。在本研究中，我们使用 C5a 受体（C5aR）拮抗剂（C5aRA）和 C5aR 阻断性单克隆抗体，研究了 C5aR 在载脂蛋白 E 缺乏型小鼠中的动脉重塑中的作用。
给予动脉粥样硬化饮食的小鼠进行颈动脉内皮剥脱的电丝损伤，并接受 C5aRA 和抗 C5aR 阻断性单克隆抗体或载体对照的治疗。与对照组相比，在接受 C5aRA 或抗 C5aR 阻断性单克隆抗体治疗 1 周的小鼠中，新生内膜形成明显减少，但在 3 周时则没有减少，这归因于血管平滑肌细胞含量增加，而单核细胞和中性粒细胞含量的显著减少与血管细胞黏附分子-1 的减少有关。免疫组织化学、逆转录聚合酶链反应和流式细胞术评估表明，C5aR 在病变和培养的血管平滑肌细胞中表达，损伤或肿瘤坏死因子-α可使其上调，并被 C5aRA 下调。损伤后 1 周时，血浆水平和新生内膜纤溶酶原激活物抑制剂-1 达到峰值，而在 C5aRA 治疗的小鼠中则降低。在体外，C5a 以 C5aRA 依赖的方式诱导内皮细胞和血管平滑肌细胞中的纤溶酶原激活物抑制剂-1 表达，这可能是血管平滑肌细胞迁移增加的原因。
C5aRA 或抗 C5aR 阻断性单克隆抗体治疗 1 周可限制新生内膜增生和炎症细胞含量，并与血管细胞黏附分子-1 表达降低有关。但是，治疗 3 周未能减少而是稳定斑块，可能是通过降低血管纤溶酶原激活物抑制剂-1 和增加血管平滑肌细胞迁移来实现的。
