Disturbed flow leads to increased inflammatory responses of endothelial cells (ECs) prone to atherogenic state. Currently, little is known about the physiological mechanisms protecting vasculature against disturbed flow-activated ECs leading to atherosclerosis. Understanding the protective mediators involved in EC activation could provide novel therapeutic strategies for atherosclerosis. The extracellular matrix microenvironment profoundly regulates cellular homeostasis. A non-EC resident ECM protein, cartilage oligomeric matrix protein (COMP), has diverse protective roles in the cardiovascular system. To determine whether COMP could protect against disturbed flow-activated EC and atherosclerosis, we compared oscillatory shear stress (OSS) induced EC activation coated with various ECM proteins. Purified COMP inhibited EC activation caused by OSS. EC activation was upregulated in the aortic arch where the flow is disturbed in COMP^−/− mice as compared with wild-type mice under physiological conditions or pathologically in partially ligated mouse carotid arteries. Mechanistically, co-immunoprecipitation, mammalian two-hybrid and FRET assay results suggest that COMP bound directly to integrin α5 via its C-terminus. We next synthesized a COMP-derived peptidomimetics (CCPep24) mimicking a specific COMP–integrin α5 interaction and found that CCPep24 protected against EC activation and atherogenesis in vivo. This study extends our current understanding of how ECM and flow coordinately fine-tune EC homeostasis and reveals the potential therapeutic effect of COMP or COMP-derived peptidomimetics on blocking aberrant integrin α5 activation, inflammatory EC activation and atherosclerosis pathogenesis.

扰动的流动会导致内皮细胞 (EC) 的炎症反应增加，容易发生动脉粥样硬化。目前，关于保护脉管系统免受干扰流动激活的 ECs 导致动脉粥样硬化的生理机制知之甚少。了解参与 EC 激活的保护介质可以为动脉粥样硬化提供新的治疗策略。细胞外基质微环境深刻地调节细胞稳态。非 EC 驻留 ECM 蛋白，软骨寡聚基质蛋白 (COMP)，在心血管系统中具有多种保护作用。为了确定 COMP 是否可以防止受干扰的流动激活的 EC 和动脉粥样硬化，我们比较了振荡剪切应力 (OSS) 诱导的 EC 激活，该激活包覆有各种 ECM 蛋白。纯化的 COMP 抑制了由 OSS 引起的 EC 激活。^-/-小鼠与生理条件下或病理上部分结扎的小鼠颈动脉中的野生型小鼠相比。从机制上讲，免疫共沉淀、哺乳动物双杂交和 FRET 测定结果表明 COMP 通过其 C 端直接与整合素 α5 结合。我们接下来合成了模拟特定 COMP-整合素 α5 相互作用的 COMP 衍生肽模拟物 (CCPep24)，并发现 CCPep24在体内防止 EC 激活和动脉粥样硬化。这项研究扩展了我们目前对 ECM 和流量如何协调微调 EC 稳态的理解，并揭示了 COMP 或 COMP 衍生的肽模拟物对阻断异常整合素 α5 激活、炎症性 EC 激活和动脉粥样硬化发病机制的潜在治疗作用。