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Hemodynamic regulation of endothelial permeability and migration.

机译：血管内皮通透性和迁移的血流动力学调节。

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摘要

Atherosclerosis is a chronic inflammatory disease that results from dysfunction in the endothelial layer. Plaques preferentially form in regions of low, oscillatory wall shear stresses and are associated with elevated permeability. Hemodynamic regulation of endothelial cell (EC) migration and permeability plays a significant role in the focal development of atherosclerosis. We developed novel tools to investigate real-time EC migration and barrier function in the presence of hemodynamic shear stress.;Hemodynamic regulation of directional EC migration implies an essential role of shear stress in governing EC polarity. Results demonstrate that the presence of mitogenic factors significantly affects the flow-induced dynamics of movement and directed migration of ECs in the flow direction. ECs exposed to arterial flow in serum/growth factor-free media and then supplemented with growth factors rapidly increased directional migration and distance traveled with the flow direction. This response was modulated by the directionality of flow and inhibited by dominant-negative Par6.;Characterizing endothelial permeability is necessary to elucidate the events that are early precursors of atherosclerosis. We developed a transwell model of permeability that incorporates a flow device to apply physiological shear stress. Shear stress induced permeability is dependent on PAK activation and localization to the cell junctions. PAK activation and flow-induced permeability are enhanced by atherogenic extracellular matrices. Endothelial barrier function was integrated with the microscope flow device to measure real-time barrier integrity with hemodynamic flow. Shear stress protects against barrier disruption by vasoactive agents. Further, atheroprone flow induces barrier disruption compared to atheroprotective flow profiles. PAK activation and association with betaPIX are necessary for shear stress induced barrier disruption.;Shear stress induced permeability is dependent on expression of beta-catenin. ECs deficient in beta-catenin are unable to demonstrate flow-induced Erk1/2 activation. Shear stress-induced PAK activation, however, was beta-catenin independent. Knockdown of f3catenin resulted in decreased activity in the PAK-betaPIX-GIT1-MEK signaling complex that activates Erk1/2. Shear stress-induced barrier response was reduced by beta-catenin knockdown. In static conditions, knockdown of beta-catenin reduced the barrier disruption stimulated by both thrombin and histamine. These data further suggest that beta-catenin regulates the signaling complex PAK-betaPIX-GIT1-MEK and downstream cell contractility.
机译：动脉粥样硬化是一种慢性炎性疾病，由内皮层功能障碍引起。斑块优选在低的，振荡的壁剪切应力的区域中形成，并且与渗透性升高有关。内皮细胞（EC）迁移和通透性的血流动力学调节在动脉粥样硬化的局灶性发展中起着重要作用。我们开发了新颖的工具来研究存在血流动力学切应力的实时EC迁移和屏障功能。定向EC迁移的血流动力学调节暗示了剪切应力在控制EC极性中的重要作用。结果表明，有丝分裂因子的存在显着影响了流动诱导的运动动力学和ECs在流动方向上的定向迁移。 ECs在无血清/无生长因子的培养基中暴露于动脉血流中，然后补充生长因子，迅速增加了方向迁移，并沿流向移动了距离。该反应受血流方向性的调节，并受显性负Par6抑制。表征内皮渗透性对于阐明动脉粥样硬化的早期先兆是必要的。我们开发了一种通透性的跨井模型，该模型结合了一种流动装置来施加生理切应力。剪切应力诱导的通透性取决于PAK活化和定位于细胞连接处。动脉粥样硬化细胞外基质可增强PAK的激活和血流诱导的通透性。内皮屏障功能与显微镜流量设备集成在一起，可通过血流动力学流量实时测量屏障的完整性。剪应力可防止血管活性剂破坏屏障。此外，与抗动脉粥样硬化的流动曲线相比，动脉粥样硬化流动引起屏障破坏。 PAK活化和与betaPIX的缔合对于剪切应力诱导的屏障破坏是必需的。剪切应力诱导的渗透性取决于β-catenin的表达。缺乏β-catenin的EC不能证明血流诱导的Erk1 / 2激活。剪应力诱导的PAK激活，但是，是β-catenin独立的。敲低f3catenin导致激活Erk1 / 2的PAK-betaPIX-GIT1-MEK信号复合物的活性降低。剪应力诱导的屏障反应减少了β-catenin组合。在静态条件下，敲低β-catenin可减少凝血酶和组胺刺激的屏障破坏。这些数据进一步表明，β-连环蛋白调节信号转导复合物PAK-betaPIX-GIT1-MEK和下游细胞的收缩力。

著录项

  • 作者

    Simmers, Michael Bennett.;

  • 作者单位

    University of Virginia.;

  • 授予单位 University of Virginia.;
  • 学科 Engineering Biomedical.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 116 p.
  • 总页数 116
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

  • 入库时间 2022-08-17 11:36:56

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