Cicha Iwona, Goppelt-Struebe Margarete, Yilmaz Atilla, Daniel Werner G, Garlichs Christoph D
Medical Clinic 2, University of Erlangen-Nuremberg, Erlangen, Germany.
Clin Hemorheol Microcirc. 2008;39(1-4):113-9.
Atherosclerosis results from a combination of local blood flow patterns and systemic risk factors. We investigated whether non-uniform shear stress at bifurcations induces pro-atherogenic endothelial dysfunction and monocyte recruitment. Bifurcating flow-through cell culture slides were used to expose HUVECs to laminar or non-uniform shear stress for 18 h at 10 dyne/cm(2). For the adhesion assay, HUVECs were subsequently perfused with medium containing THP-1 monocytes for 1 h. Protein expression was determined by immunofluorescence. In areas exposed to laminar shear stress, alignment of endothelial cells with the flow was observed, accompanied by upregulation of eNOS and downregulation of connective tissue growth factor (CTGF). In contrast, cells exposed to non-uniform shear stress near the outer walls of bifurcations were characterized by irregular, unaligned shape, induction of endothelin-1 and CTGF, as well as reduced eNOS expression. These atherogenic effects of non-uniform shear stress were prevented when cells were treated with statins (1 mumol/l) during flow. Under non-uniform shear stress, a slight induction of VCAM-1, ICAM-1, and E-/P-selectin was observed. In agreement with this, monocyte recruitment, which was nearly undetectable under laminar shear stress, was moderately induced by non-uniform shear stress (P<0.02). In conclusion, inhibition of antioxidative eNOS and upregulation of atherogenic proteins is the first step in non-uniform shear stress-mediated endothelial dysfunction, which in vivo in the presence of atherogenic risk factors may further enhance monocyte recruitment into the artery wall.
动脉粥样硬化是局部血流模式和全身风险因素共同作用的结果。我们研究了分叉处的非均匀剪切应力是否会诱导促动脉粥样硬化的内皮功能障碍和单核细胞募集。使用分叉式流通细胞培养载玻片，在10达因/平方厘米的条件下，将人脐静脉内皮细胞（HUVECs）暴露于层流或非均匀剪切应力下18小时。对于黏附试验，随后用含有THP-1单核细胞的培养基灌注HUVECs 1小时。通过免疫荧光法测定蛋白质表达。在暴露于层流剪切应力的区域，观察到内皮细胞与血流方向一致，同时内皮型一氧化氮合酶（eNOS）上调，结缔组织生长因子（CTGF）下调。相反，在分叉外壁附近暴露于非均匀剪切应力的细胞表现为形状不规则、排列不齐，内皮素-1和CTGF诱导表达，同时eNOS表达降低。当细胞在流动过程中用他汀类药物（1微摩尔/升）处理时，非均匀剪切应力的这些促动脉粥样硬化作用被阻止。在非均匀剪切应力下，观察到血管细胞黏附分子-1（VCAM-1）、细胞间黏附分子-1（ICAM-1）和E-/P-选择素略有诱导表达。与此一致的是，在层流剪切应力下几乎检测不到的单核细胞募集，在非均匀剪切应力作用下被适度诱导（P<0.02）。总之，抗氧化性eNOS的抑制和促动脉粥样硬化蛋白的上调是非均匀剪切应力介导的内皮功能障碍的第一步，在存在动脉粥样硬化风险因素的体内，这可能会进一步增强单核细胞向动脉壁的募集。
