Mechanotransduction-on-chip: vessel-chip model of endothelial YAP mechanobiology reveals matrix stiffness impedes shear response.
Mechanotransduction-on-chip: vessel-chip model of endothelial YAP mechanobiology reveals matrix stiffness impedes shear response.
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DOI：
10.1039/d0lc01283a
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发表时间：
2021-05-04
期刊：
影响因子：
6.1
通讯作者：
中科院分区：
文献类型：
--
作者：
内皮机械生物学是血管功能障碍（包括动脉粥样硬化）进展的关键因素。然而，临床相关的物理刺激，血管硬度和剪切应力，以及它们如何相互作用，以调节斑块进展之间的机械连接仍然不完全的特点。血管-芯片系统是用于建模血管机械生物学的优秀候选者，因为它们可以在人体动脉和静脉中存在的机械参数的指导下从头开始设计，以概括脉管系统的关键特征。在这里，我们报告了广泛的验证血管芯片模型的内皮是相关蛋白（雅普）的机械生物学，一种蛋白质敏感的基质硬度和剪切力，重要的是，在动脉粥样硬化的进展。我们的模型捕获了已建立的内皮机械反应，在高层流剪切下内皮对齐、伸长、粘附分子减少和雅普细胞质保留。相反，我们观察到扰动形态，炎症，核分区低，高，高振荡剪切。检查雅普转录共激活的靶标，结缔组织生长因子（CTGF）被高层流剪切强烈下调，而被低剪切或振荡流强烈上调。锚蛋白重复结构域1（ANKRD 1）仅通过高振荡剪切上调。维替泊芬抑制雅普可降低CTGF的表达，但不影响ANKRD 1。最后，基板刚度调制的内皮剪切机械响应。在高剪切下，较软的基板表现出最低的核定位的雅普，而较硬的基板增加核定位。低剪切力强烈地增加了雅普在整个硬度上的核定位。总之，我们已经验证了内皮机械生物学模型，并通过雅普机械生物学描述了基质硬度、剪切应力和内皮激活之间的临床相关生物学联系。
Endothelial mechanobiology is a key consideration in the progression of vascular dysfunction, including atherosclerosis. However mechanistic connections between the clinically associated physical stimuli, vessel stiffness and shear stress, and how they interact to modulate plaque progression remain incompletely characterized. Vessel-chip systems are excellent candidates for modeling vascular mechanobiology as they may be engineered from the ground up, guided by the mechanical parameters present in human arteries and veins, to recapitulate key features of the vasculature. Here, we report extensive validation of a vessel-chip model of endothelial yes-associated protein (YAP) mechanobiology, a protein sensitive to both matrix stiffness and shearing forces and, importantly, implicated in atherosclerotic progression. Our model captures the established endothelial mechanoresponse, with endothelial alignment, elongation, reduction of adhesion molecules, and YAP cytoplasmic retention under high laminar shear. Conversely, we observed disturbed morphology, inflammation, and nuclear partitioning under low, high, and high oscillatory shear. Examining targets of YAP transcriptional co-activation, connective tissue growth factor (CTGF) is strongly downregulated by high laminar shear, whereas it is strongly upregulated by low shear or oscillatory flow. Ankyrin repeat domain 1 (ANKRD1) is only upregulated by high oscillatory shear. Verteporfin inhibition of YAP reduced the expression of CTGF but did not affect ANKRD1. Lastly, substrate stiffness modulated the endothelial shear mechanoresponse. Under high shear, softer substrates showed the lowest nuclear localization of YAP whereas stiffer substrates increased nuclear localization. Low shear strongly increased nuclear localization of YAP across stiffnesses. Together, we have validated a model of endothelial mechanobiology and describe a clinically relevant biological connection between matrix stiffness, shear stress, and endothelial activation via YAP mechanobiology.
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影响因子：
20.1
作者：
Diamond SL
通讯作者：
Diamond SL
用于研究药物输送系统的器官片平台。
DOI：
10.1016/j.jconrel.2014.05.004
发表时间：
2014-09-28
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Bhise NS;Ribas J;Manoharan V;Zhang YS;Polini A;Massa S;Dokmeci MR;Khademhosseini A
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Khademhosseini A
影响因子：
46.9
作者：
Bhatia, Sangeeta N.;Ingber, Donald E.
通讯作者：
Ingber, Donald E.
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影响因子：
4
作者：
Dominic A;Hamilton D;Abe JI
通讯作者：
Abe JI
影响因子：
33.6
作者：
Chiu JJ;Chien S
通讯作者：
Chien S