State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China.
Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Atherosclerosis. 2024 Dec;399:118586. doi: 10.1016/j.atherosclerosis.2024.118586. Epub 2024 Oct 23.
Vascular restenosis due to neointima hyperplasia limits the long-term patency of stented arteries, resulting in angioplasty failure. The complement system has been implicated in restenosis. This study aimed to investigate the role of complement factor B (fB), an essential component of the alternative pathway of complement activation, in neointima formation.
Angioplasty wire injury was conducted using 12-week-old mice deficient in fB or C9 (the main component of the membrane attacking complex, C5b-9) and littermate controls and neointima formation were assessed. Vascular smooth muscle cell (SMC) and endothelial cell (EC) proliferation and migration were examined in vitro.
fB was mainly detected in SMCs of stenotic arteries from humans and mice. Deletion of fB substantially reduced the neointima area and intima-to-media area ratio without affecting the media area at 28 days after injury. At 7 days after injury, fB deficiency decreased SMC proliferation, unaltering neointimal macrophage infiltration and EC reendothelialization. Vascular SMC-expressed fB, not the circulation-sourced fB, played an essential role in SMC proliferation and migration in vitro. fB deficient mice exhibited lower levels of the soluble form of C5b-9, however, deletion of C9 did not alter neointima formation after wire injury, consistent with the null impact of C9 deficiency on SMC proliferation in vitro.
fB promotes neointima formation following wire-induced artery injury independent of forming the membrane-attacking complex. This is attributable to fB-dependent SMC proliferation and migration without affecting EC function. Targeting fB might protect against restenosis after percutaneous coronary intervention.
新生内膜过度增生导致的血管再狭窄限制了支架血管的长期通畅性，从而导致血管成形术失败。补体系统与再狭窄有关。本研究旨在探讨补体因子 B（fB）在新生内膜形成中的作用，fB 是补体激活替代途径的必需成分。
使用 12 周龄缺乏 fB 或 C9（膜攻击复合物的主要成分 C5b-9）的基因敲除小鼠及其同窝对照进行球囊血管成形术损伤，并评估新生内膜形成。体外检测血管平滑肌细胞（SMC）和内皮细胞（EC）增殖和迁移。
fB 主要在人类和小鼠狭窄动脉的 SMC 中检测到。fB 缺失显著减少了 28 天后的新生内膜面积和内膜-中膜面积比，而不影响中膜面积。损伤后 7 天，fB 缺失减少了 SMC 增殖，不改变新生内膜巨噬细胞浸润和 EC 再内皮化。血管 SMC 表达的 fB，而不是循环来源的 fB，在体外对 SMC 增殖和迁移起关键作用。fB 缺失小鼠可溶性 C5b-9 水平较低，但 C9 缺失并不改变血管损伤后的新生内膜形成，这与 C9 缺失对体外 SMC 增殖无影响一致。
fB 独立于形成膜攻击复合物促进球囊诱导的动脉损伤后的新生内膜形成。这归因于 fB 依赖性 SMC 增殖和迁移，而不影响 EC 功能。靶向 fB 可能有助于预防经皮冠状动脉介入治疗后的再狭窄。
