Chappell D C, Varner S E, Nerem R M, Medford R M, Alexander R W
Department of Medicine, Emory University, Atlanta, GA, USA.
Circ Res. 1998 Mar 23;82(5):532-9. doi: 10.1161/01.res.82.5.532.
Low and oscillatory shear stresses are major features of the hemodynamic environment of sites opposite arterial flow dividers that are predisposed to atherosclerosis. Atherosclerosis is a focal inflammatory disease characterized initially by the recruitment of mononuclear cells into the arterial wall. The specific characteristics of the hemodynamic environment that facilitate the generation of arterial inflammatory responses in the presence of, for example, hyperlipidemia are unknown. We show here that prolonged oscillatory shear stress induces expression of endothelial cell leukocyte adhesion molecules, which are centrally important in mediating leukocyte localization into the arterial wall. Vascular cell adhesion molecule-1 was upregulated an average 9-fold relative to endothelial monolayers in static culture. Intercellular adhesion molecule-1 and E-selectin exhibited 11-fold and 7.5-fold increases, respectively. Upregulation of these adhesion molecules was associated with enhanced monocyte adherence. Cytokine stimulation of surface vascular cell adhesion molecule-1 was maximally induced after 6 and 8 hours of cytokine incubation. Oscillatory shear stress for these time periods elicited respective vascular cell adhesion molecule-1 levels of 16% and 30% relative to those observed for cytokine stimulation. Surface intercellular adhesion molecule-1 induction by cytokine stimulation for 24 hours was found to be approximately five times the level detected after 24 hours of oscillatory shear stress. Experiments performed in the presence of the antioxidant N-acetylcysteine demonstrated that the expression of vascular cell adhesion molecule-1 could be almost totally abolished, whereas that of intercellular adhesion molecule-1 was typically reduced by approximately 70%. These results imply that oscillatory shear stress per se is sufficient to stimulate mononuclear leukocyte adhesion and, presumptively, migration into the arterial wall. These results further indicate that atherosclerotic lesion initiation is likely related, at least in part, to unique signals generated by oscillatory shear stress and that the mechanism of upregulation is, to some extent, redox sensitive.
低剪切应力和振荡剪切应力是易于发生动脉粥样硬化的动脉血流分流器相对部位血流动力学环境的主要特征。动脉粥样硬化是一种局灶性炎症性疾病，最初表现为单核细胞募集到动脉壁。例如，在存在高脂血症的情况下，促进动脉炎症反应产生的血流动力学环境的具体特征尚不清楚。我们在此表明，长时间的振荡剪切应力可诱导内皮细胞白细胞粘附分子的表达，这在介导白细胞定位到动脉壁中起着核心重要作用。相对于静态培养中的内皮单层，血管细胞粘附分子-1平均上调了9倍。细胞间粘附分子-1和E-选择素分别增加了11倍和7.5倍。这些粘附分子的上调与单核细胞粘附增强有关。细胞因子孵育6小时和8小时后，表面血管细胞粘附分子-1的细胞因子刺激达到最大诱导。在这些时间段的振荡剪切应力分别引起相对于细胞因子刺激观察到的血管细胞粘附分子-1水平的16%和30%。发现细胞因子刺激24小时诱导的表面细胞间粘附分子-1约为振荡剪切应力24小时后检测水平的五倍。在抗氧化剂N-乙酰半胱氨酸存在下进行的实验表明，血管细胞粘附分子-1的表达几乎可以完全消除，而细胞间粘附分子-1的表达通常降低约70%。这些结果表明，振荡剪切应力本身足以刺激单核白细胞粘附，并推测其迁移到动脉壁中。这些结果进一步表明，动脉粥样硬化病变的起始可能至少部分与振荡剪切应力产生的独特信号有关，并且上调机制在一定程度上对氧化还原敏感。
