National Centre for Biomedical Engineering Science, National University of Ireland Galway, Galway, Ireland.
Ann Biomed Eng. 2010 May;38(5):1880-92. doi: 10.1007/s10439-010-9959-8. Epub 2010 Feb 17.
Previous mechano-transduction studies have investigated the endothelial cell (EC) morphological response to mechanical stimuli; generally consisting of a wall shear stress (WSS) and a cyclic tensile hoop strain (THS). More recent studies have investigated the EC biochemical response (intercellular adhesion molecule, ICAM-1, and vascular cellular adhesion molecule, VCAM-1, expression) to idealized mechanical stimuli. However, current literature is lacking in the area of EC biochemical response to combinations of physiological WSS and THS mechanical stimuli. The objective of this study is to investigate the EC response to physiological WSS and THS stimuli and to compare this response to that of ECs exposed to idealized steady WSS and cyclic THS of the same magnitudes. This study also investigated the EC response to a nicotine chemical stimulus combined with a suspected athero-prone physiological mechanical stimulus. A bioreactor was designed to apply a range of combinations of physiological WSS and THS waveforms. The bioreactor was calibrated and validated using computational fluid dynamics and video extensometry techniques. The bioreactor was used to investigated the biochemical response exhibited by human umbilical vein endothelial cells (HUVECs) exposed to physiological athero-protective (first bioreactor test case, pulsatile WSS combined with pulsatile THS) and athero-prone (second bioreactor test case, oscillating WSS combined with pulsatile THS) mechanical environments. The final testing environment (third bioreactor test case) combined a nicotine chemical stimulus with the mechanical stimuli of the second bioreactor test case. In first and second bioreactor test cases, the addition of a pulsatile THS to the WSS resulted in opposite trends of ICAM-1 down-regulation and up-regulation, respectively. This outcome suggests that the effect of the additional pulsatile THS depends on the state of the applied WSS waveform. Similarly, in first and second bioreactor test cases, the addition of a pulsatile THS to the WSS resulted in a VCAM-1 up-regulation. However, it has been previously shown that the addition of a cyclic THS to a high- or low-steady WSS resulted in a VCAM-1 down-regulation, indicating that the EC response to idealized mechanical stimuli (steady WSS and cyclic THS) is not comparable to physiological mechanical stimuli (unsteady WSS and pulsatile THS), even though in both situations the average magnitude of WSS and THS applied were similar. In third bioreactor test case, a nicotine chemical stimulus induced a substantial VCAM-1 up-regulation and a moderate ICAM-1 up-regulation. The addition of the mechanical stimuli of the second bioreactors test case resulted in a greater VCAM-1 up-regulation than what was expected, considering the observations of the previous second bioreactor test case alone. This study found that the EC biochemical response to physiological mechanical stimuli is not comparable to the previously observed EC response to idealized mechanical stimuli, even though in both environments the mechanical stimuli were of a similar magnitude. Also, the level of VCAM-1 expressed by the nicotine stimulated ECs showed an elevated level of sensitivity to the athero-prone mechanical stimuli.
先前的机械转导研究调查了内皮细胞（EC）对机械刺激的形态响应；一般包括壁面切应力（WSS）和循环拉伸环向应变（THS）。最近的研究调查了 EC 的生化反应（细胞间黏附分子 1（ICAM-1）和血管细胞黏附分子 1（VCAM-1）的表达）对理想化的机械刺激。然而，目前的文献在 EC 对生理 WSS 和 THS 机械刺激组合的生化反应方面存在不足。本研究旨在调查 EC 对生理 WSS 和 THS 刺激的反应，并将其与暴露于相同幅度理想化稳态 WSS 和循环 THS 的 EC 的反应进行比较。本研究还调查了 EC 对尼古丁化学刺激与可疑动脉粥样硬化倾向生理机械刺激的联合反应。设计了一个生物反应器来施加一系列生理 WSS 和 THS 波形的组合。使用计算流体动力学和视频伸长计技术对生物反应器进行了校准和验证。该生物反应器用于研究暴露于生理动脉粥样硬化保护（第一生物反应器测试案例，脉动 WSS 与脉动 THS 结合）和动脉粥样硬化倾向（第二生物反应器测试案例，振荡 WSS 与脉动 THS 结合）机械环境的人脐静脉内皮细胞（HUVEC）表现出的生化反应。最终测试环境（第三生物反应器测试案例）将尼古丁化学刺激与第二生物反应器测试案例的机械刺激相结合。在第一和第二生物反应器测试案例中，在 WSS 中添加脉动 THS 分别导致 ICAM-1 下调和上调的相反趋势。这一结果表明，附加脉动 THS 的效果取决于所施加 WSS 波形的状态。同样，在第一和第二生物反应器测试案例中，在 WSS 中添加脉动 THS 导致 VCAM-1 上调。然而，先前已经表明，在高或低稳态 WSS 中添加循环 THS 会导致 VCAM-1 下调，表明 EC 对理想化机械刺激（稳态 WSS 和循环 THS）的反应与生理机械刺激（非稳态 WSS 和脉动 THS）不同，尽管在这两种情况下，施加的 WSS 和 THS 的平均幅度相似。在第三生物反应器测试案例中，尼古丁化学刺激诱导了 VCAM-1 的大量上调和 ICAM-1 的适度上调。添加第二生物反应器测试案例的机械刺激导致 VCAM-1 的上调程度大于仅考虑第二生物反应器测试案例的观察结果所预期的程度。本研究发现，EC 对生理机械刺激的生化反应与之前观察到的对理想化机械刺激的 EC 反应不同，尽管在这两种环境中，机械刺激的幅度相似。此外，尼古丁刺激的 EC 表达的 VCAM-1 水平对动脉粥样硬化倾向的机械刺激表现出更高的敏感性。
