Complement-mediated inhibition of neovascularization reveals a point of convergence between innate immunity and angiogenesis
Complement-mediated inhibition of neovascularization reveals a point of convergence between innate immunity and angiogenesis
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DOI：
10.1182/blood-2010-01-261503
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发表时间：
2010-11-25
期刊：
影响因子：
20.3
通讯作者：
Chavakis, Triantafyllos
中科院分区：
文献类型：
--
作者：
Langer, Harald F.;Chung, Kyoung-Jin;Chavakis, Triantafyllos
除了其在免疫中的作用之外，补体在形态发生或组织重塑过程的背景下介导广泛的功能。血管生成在多种病理的组织重塑过程中是至关重要的;然而，关于补体成分对新血管形成的调节的知识是稀缺的。在这里，我们研究了补体参与病理性血管生成。引人注目的是，我们发现，在中心补体成分C3缺乏的小鼠显示增加的新生血管在早产儿视网膜病变（ROP）模型和在体内基质胶塞测定。此外，抗体介导的C5阻断、C5 aR拮抗剂治疗或C5 aR缺陷导致小鼠病理性视网膜血管生成增强。虽然补体没有直接影响血管生成相关的内皮细胞功能，我们发现巨噬细胞介导的补体的抗血管生成活性。特别是，C5 a刺激的巨噬细胞被极化向血管生成抑制表型，包括上调分泌的抗血管生成可溶性血管内皮生长因子受体-1。一致地，体内巨噬细胞耗竭逆转了与C3-或C5 aR缺乏相关的新血管形成增加。总之，补体，特别是C5 a-C5 aR轴是血管生成的有效抑制剂。（血。2010;116（22）：4395-4403）
Beyond its role in immunity, complement mediates a wide range of functions in the context of morphogenetic or tissue remodeling processes. Angiogenesis is crucial during tissue remodeling in multiple pathologies; however, the knowledge about the regulation of neovascularization by the complement components is scarce. Here we studied the involvement of complement in pathological angiogenesis. Strikingly, we found that mice deficient in the central complement component C3 displayed increased neovascularization in the model of retinopathy of prematurity (ROP) and in the in vivo Matrigel plug assay. In addition, antibody-mediated blockade of C5, treatment with C5aR antagonist, or C5aR deficiency in mice resulted in enhanced pathological retina angiogenesis. While complement did not directly affect angiogenesis-related endothelial cell functions, we found that macrophages mediated the antiangiogenic activity of complement. In particular, C5a-stimulated macrophages were polarized toward an angiogenesis-inhibitory phenotype, including the up-regulated secretion of the antiangiogenic soluble vascular endothelial growth factor receptor-1. Consistently, macrophage depletion in vivo reversed the increased neovascularization associated with C3- or C5aR deficiency. Taken together, complement and in particular the C5a-C5aR axes are potent inhibitors of angiogenesis. (Blood. 2010;116(22):4395-4403)