Liu Zhu Hui, Li Chang, Chen Jia Wei, Shen Ying, Gao Jie, Shen Wei Feng, Zhang Rui Yan, Wang Xiao Qun, Lu Lin
Department of Cardiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; Institute of Cardiovascular Diseases, Shanghai Jiao Tong University, Shanghai, PR China.
Department of Cardiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
Biochem Biophys Res Commun. 2017 Aug 19;490(2):580-586. doi: 10.1016/j.bbrc.2017.06.081. Epub 2017 Jun 15.
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 C1q/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.
内皮细胞高通透性是导致血流动力学紊乱部位动脉粥样硬化病变加速发展的一个主要决定因素。此前，我们发现C1q/TNF相关蛋白（CTRP）1可促进血管细胞中的内皮细胞与白细胞相互作用及炎症反应。在此，我们试图研究CTRP1在紊乱血流条件下对内皮通透性调节中的作用。通过对小鼠主动脉进行正面染色，我们发现与稳定层流相比，紊乱血流条件下血管内皮细胞中CTRP1的表达显著增加。与野生型动物相比，CTRP1基因敲入小鼠对伊文思蓝染料的血管通透性显著增强，而在敲除CTRP1后，紊乱部位的主动脉高通透性明显恢复。在培养的内皮细胞中，CTRP1处理导致对荧光标记葡聚糖的通透性增加，并出现与紊乱血流暴露后观察到的类似的细胞间孔形成，而在存在CTRP1特异性中和抗体的情况下，这种情况明显减少。从机制上讲，我们发现CTRP1对VEGFR2的激活可能参与了紊乱血流条件下的血管高通透性。综上所述，本研究表明CTRP1是一种机械敏感的促炎因子，介导紊乱血流诱导的血管屏障功能障碍。抑制CTRP1可能在早期抑制动脉粥样硬化的发病机制。
