C1q/TNF-related protein 1 promotes endothelial barrier dysfunction under disturbed flow
C1q/TNF-related protein 1 promotes endothelial barrier dysfunction under disturbed flow
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C1q/TNF相关蛋白1在血流紊乱下促进内皮屏障功能障碍
DOI：
10.1016/j.bbrc.2017.06.081
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发表时间：
2017-08-19
影响因子：
3.1
通讯作者：
Lu, Lin
中科院分区：
文献类型：
--
作者：
Liu, Zhu Hui;Li, Chang;Lu, Lin
内皮细胞高通透性是血流动力学紊乱部位动脉粥样硬化病变加速发展的主要决定因素。以前，我们发现Clq/TNF相关蛋白（CTRP）1促进血管细胞中的内皮-白细胞相互作用和炎症反应。在这里，我们试图研究CTRP 1在扰动流条件下调节内皮通透性的作用。通过使用小鼠主动脉的表面染色，我们发现与稳定层流相比，在扰动流下血管内皮细胞中CTRP 1的表达显著增加。与野生型动物相比，CTRP 1敲入小鼠中血管对伊文思蓝染料的通透性显著增强，而在CTRP 1缺失后，受干扰部位的主动脉高通透性显著恢复。在培养的内皮细胞中，CTRP 1的治疗导致荧光标记的葡聚糖的渗透性增加，并在干扰流暴露后观察到明显形成细胞旁孔，这在CTRP 1特异性中和抗体的存在下明显减少。从机制上讲，我们发现CTRP 1激活VEGFR 2可能参与了扰动流条件下血管通透性增高。总之，这项研究表明，CTRP 1是一种机械敏感的促炎因子，介导干扰流量引起的血管屏障功能障碍。抑制CTRP 1可能在早期抑制动脉粥样硬化的发病。(C)2017爱思唯尔公司All rights reserved.
Endothelial hyper-permeability is a major determinant factor that contributes to the accelerated development of atherosclerotic lesions at hemodynamically disturbed sites. Previously, we showed that Clq/TNF related protein (CTRP) 1 promotes endothelium-leukocyte interactions and inflammatory responses in vascular cells. Here, we sought to investigate the role of CTRP1 in modulation of endothelial permeability under disturbed flow condition. By using en face staining of mouse aorta, we found CTRP1 expression was significantly increased in vascular endothelial cells under disturbed flow as compared to steady laminar flow. Vascular permeability to Evans blue dye was notably enhanced in CTRP1 knockin mice as compared to wild type animals, whereas aortic hyper-permeability at disturbed sites was remarkably restored after deletion of CTRP1. In cultured endothelial cells, treatment of CTRP1 led to increased permeability to fluorescent-labelled dextran and apparent formation of paracellular holes as observed after disturbed flow exposure, which was evidently reduced in the presence of a CTRP1-specific neutralizing antibody. Mechanistically, we found activation of VEGFR2 by CTRP1 might be involved in vascular hyper-permeability under disturbed flow condition. Taken together, this study suggests that CTRP1 is a mechano-sensitive proinflammatory factor that mediates disturbed flow-induced vascular barrier dysfunction. Inhibition of CTRP1 may inhibit the pathogenesis of atherosclerosis at early stage. (C) 2017 Elsevier Inc. All rights reserved.