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首页> 外文期刊>Journal of Biomechanics >OxLDL and substrate stiffness promote neutrophil transmigration by enhanced endothelial cell contractility and ICAM-1
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OxLDL and substrate stiffness promote neutrophil transmigration by enhanced endothelial cell contractility and ICAM-1

机译：OxLDL和底物硬度通过增强内皮细胞收缩力和ICAM-1促进中性粒细胞迁移

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摘要

Elevated levels of oxLDL in the bloodstream and increased vasculature stiffness are both associated with cardiovascular disease in patients. However, it is not known how oxLDL and subendothelial matrix stiffness together regulate an immune response. Here, we used an in vitro model of the vascular endothelium to explore the combined effects of oxLDL and subendothelial matrix stiffening on neutrophil transmigration. We prepared fibronectin-coated polyacrylamide gels of varying stiffness and plated human umbilical vein endothelial cells (ECs) onto the gels. We observed that oxLDL treatment of the endothelium promoted neutrophil transmigration (from <1% to 26% on soft 0.87. kPa substrates), with stiffer substrates further promoting transmigration (54% on 5. kPa and 41% on 280. kPa). OxLDL exposure enhanced intercellular adhesion molecule-1 (ICAM-1) expression on the endothelium, which was likely responsible for the oxLDL-induced transmigration. Importantly, inhibition of MLCK-mediated EC contraction reduced transmigration to ~9% on all substrates and eliminated the effects of subendothelial matrix stiffness. In addition, large holes, thousands of square microns in size, formed in monolayers on stiff substrates following transmigration, indicating that oxLDL treatment and subsequent neutrophil transmigration caused serious damage to the endothelium. Our results reveal that an interplay between ICAM-1 and MLCK-dependent contractile forces mediates neutrophil transmigration through oxLDL-treated endothelium. Thus, microvasculature stiffness, which likely varies depending on tissue location and health, is an important regulator of the transmigration step of the immune response in the presence of oxLDL.
机译：血液中oxLDL水平升高和脉管系统僵硬程度增加均与患者的心血管疾病有关。然而，还不知道oxLDL和内皮下基质硬度如何一起调节免疫反应。在这里，我们使用了血管内皮细胞的体外模型来探索oxLDL和内皮下基质增强对嗜中性粒细胞迁移的联合作用。我们制备了具有不同刚度的纤连蛋白涂层聚丙烯酰胺凝胶，并将人脐静脉内皮细胞（EC）铺在凝胶上。我们观察到，oxLDL内皮处理促进了嗜中性白细胞的迁移（在柔软的0.87.kPa基质上从<1％增至26％），更坚硬的基质进一步促进了迁移（在5.kPa上为54％，在280.kPa上为41％）。 OxLDL暴露增强了内皮细胞间粘附分子1（ICAM-1）的表达，这可能是oxLDL诱导的迁移的原因。重要的是，抑制MLCK介导的EC收缩可使在所有底物上的迁移减少至〜9％，并消除了内皮下基质硬度的影响。此外，在迁移后，在刚性基底上的单层中形成了数千个大孔，大小为数千平方微米，这表明oxLDL处理和随后的嗜中性白细胞迁移对内皮造成了严重损害。我们的结果表明，ICAM-1和MLCK依赖的收缩力之间的相互作用介导了通过oxLDL处理的内皮细胞的中性粒细胞迁移。因此，在存在oxLDL的情况下，微脉管的刚度可能根据组织的位置和健康状况而变化，是免疫应答的迁移步骤的重要调节剂。

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