Babendreyer Aaron, Molls Lisa, Dreymueller Daniela, Uhlig Stefan, Ludwig Andreas
Institute of Pharmacology and Toxicology, RWTH Aachen University, Aachen, Germany.
Mediators Inflamm. 2017;2017:1515389. doi: 10.1155/2017/1515389. Epub 2017 Mar 26.
Flow conditions critically regulate endothelial cell functions in the vasculature. Reduced shear stress resulting from disturbed blood flow can drive the development of vascular inflammatory lesions. On endothelial cells, the transmembrane chemokine CX3CL1/fractalkine promotes vascular inflammation by functioning as a surface-expressed adhesion molecule and by becoming released as soluble chemoattractant for monocytic cells expressing the receptor CX3CR1. Here, we report that endothelial cells from human artery, vein, or microvasculature constitutively express CX3CL1 when cultured under static conditions. Stimulation with TNF under static or very low shear stress conditions strongly upregulates CX3CL1 expression. By contrast, CX3CL1 induction is profoundly reduced when cells are exposed to higher shear stress. When endothelial cells were grown and subsequently stimulated with TNF under low shear stress, strong adhesion of monocytic THP-1 cells to endothelial cells was observed. This adhesion was in part mediated by transmembrane CX3CL1 as demonstrated with a neutralizing antibody. By contrast, no CX3CL1-dependent adhesion to stimulated endothelium was observed at high shear stress. Thus, during early stages of vascular inflammation, low shear stress typically seen at atherosclerosis-prone regions promotes the induction of endothelial CX3CL1 and monocytic cell recruitment, whereas physiological shear stress counteracts this inflammatory activation of endothelial cells.
血流状态对脉管系统中内皮细胞的功能起着关键的调节作用。血流紊乱导致的剪切应力降低可促使血管炎性病变的发展。在内皮细胞上，跨膜趋化因子CX3CL1/ fractalkine通过作为表面表达的黏附分子发挥作用，并作为表达受体CX3CR1的单核细胞的可溶性趋化因子释放，从而促进血管炎症。在此，我们报道，当在静态条件下培养时，来自人动脉、静脉或微血管的内皮细胞组成性表达CX3CL1。在静态或极低剪切应力条件下用肿瘤坏死因子（TNF）刺激可强烈上调CX3CL1的表达。相比之下，当细胞暴露于较高剪切应力时，CX3CL1的诱导则显著降低。当内皮细胞生长并随后在低剪切应力下用TNF刺激时，观察到单核THP-1细胞与内皮细胞的强烈黏附。如用中和抗体所证实的，这种黏附部分是由跨膜CX3CL1介导的。相比之下，在高剪切应力下未观察到对受刺激内皮的CX3CL1依赖性黏附。因此，在血管炎症的早期阶段，动脉粥样硬化易患区域常见的低剪切应力促进内皮CX3CL1的诱导和单核细胞募集，而生理剪切应力则抵消内皮细胞的这种炎症激活。
