Shear stress-stimulated endothelial cells induce smooth muscle cell chemotaxis via platelet-derived growth factor-BB and interleukin-1α
Shear stress-stimulated endothelial cells induce smooth muscle cell chemotaxis via platelet-derived growth factor-BB and interleukin-1α
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DOI：
10.1016/j.jvs.2004.11.016
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发表时间：
2005-02-01
影响因子：
4.3
通讯作者：
Sumpio, BE
中科院分区：
文献类型：
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作者：
Dardik, A;Yamashita, A;Sumpio, BE
目的：血管平滑肌细胞(SMC)迁移在动脉粥样硬化和新生内膜增生的发生发展中起重要作用。切应力和循环应变等血流动力刺激内皮细胞信号转导通路，导致多种因子的分泌，包括SMC趋化因子，如血小板衍生生长因子(PDGF)。我们假设机械力刺激内皮细胞分泌SMC趋化物质，通过丝裂原活化蛋白激酶(MAPK)途径诱导迁移。将牛主动脉内皮细胞暴露在切应力、循环应变或静态条件下16小时。将得到的条件培养液用作Boyden小室中的SMC化学诱导剂。Western印迹法检测SMC细胞外信号调节蛋白激酶1/2(ERK1/2)的激活情况。用抗PDGF-BB或抗IL-1α抗体或ERK1/2上游通路抑制剂PD98059抑制该通路。内皮细胞的条件培养液暴露在与动脉切应力水平相对应的剪应力下，刺激SMC迁移，但较低水平的剪应力或循环应变不能刺激SMC迁移。剪切力刺激内皮细胞将PDGF-BB和IL-1α分泌到条件培养液中。PDGF-BB和IL-1a均可促进SMC趋化作用，但两者无协同作用，均可促进SMC ERK1/2的磷酸化。结论：剪切力刺激内皮细胞分泌多种SMC趋化因子，包括PDGF-BB和IL-1α；PDGF-BB和IL-1α均通过ERK1/2信号转导途径刺激SMC趋化。这些结果表明，对血管损伤的反应可能有一条符合药物操作的共同途径。
Objective: Vascular smooth muscle cell (SMC) migration is critical to the development of atherosclerosis and neointimal hyperplasia. Hemodynamic forces such as shear stress and cyclic strain stimulate endothelial cell signal-transduction pathways, resulting in the secretion of several factors, including SMC chemoattractants such as platelet-derived growth factor (PDGF). We hypothesized that mechanical forces stimulate endothelial cells to secrete SMC chemoattractants to induce migration via the mitogen-activated protein kinase (MAPK) pathway.Methods. Bovine aortic endothelial cells were exposed to shear stress, cyclic strain, or static conditions for 16 hours. The resulting conditioned medium was used as a SMC chemoattractant in a Boyden chamber. Activation of SMC extracellular signal-regulated protein kinase 1/2 (ERK1/2) was assessed by Western blot analysis. Pathways were inhibited with anti-PDGF-BB or anti-interleukin-1 alpha (IL-1 alpha) antibodies, or the ERK1/2 upstream pathway inhibitor PD98059.Results. Conditioned medium from endothelial cells exposed to shear stress corresponding to arterial levels of shear stress stimulated SMC migration but lower levels of shear stress or cyclic strain did not. Both PDGF-BB and IL-1 alpha were secreted into the conditioned medium by endothelial cells stimulated with shear stress. Both PDGF-BB and IL-1a, stimulated SMC chemotaxis but were not synergistic, and both stimulated SMC ERK1/2 phosphorylation. Inhibition of PDGF-BB or IL-1 alpha inhibited SMC chemotaxis and ERK1/2 phosphorylation.Conclusion: Shear stress stimulates endothelial cells to secrete several SMC chemoattractants, including PDGF-BB and IL-1 alpha; both PDGF-BB and IL-1 alpha stimulate SMC chemotaxis via the ERK1/2 signal-transduction pathway. These results suggest that the response to vascular injury may have a common pathway amenable to pharmacologic manipulation.