Principal mode of Syndecan-4 mechanotransduction for the endothelial glycocalyx is a scissor-like dimer motion
Principal mode of Syndecan-4 mechanotransduction for the endothelial glycocalyx is a scissor-like dimer motion
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DOI：
10.1111/apha.13376
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发表时间：
2019-10-03
影响因子：
6.3
通讯作者：
Ventikos, Yiannis
中科院分区：
文献类型：
--
作者：
Jiang, Xi Zhuo;Luo, Kai H.;Ventikos, Yiannis
目的血管内皮细胞糖基化终末产物(EG)在心血管疾病、肾脏疾病等多种疾病中发挥重要作用。几十年来，EG作为一种将机械信号传递到细胞质的机械换能器的一个标志性功能已经被记录在案。然而，基本的问题--糖基化如何传递流动剪切力--到目前为止还没有答案。我们的目的是阐明从血流到内皮细胞骨架的信号传递的基本模式。方法通过一系列大规模的分子动力学计算实验，研究不同条件下(血流速度变化和糖链脱落)下的糖萼动力学。结果发现该系统中信号传递的主要途径是Syndecan-4核心蛋白的剪刀式运动。结果表明，传递到细胞骨架的力的量级类似于100pN，糖萼元件的糖链的主要功能是保护核心蛋白免受严重构象变化的影响，从而维持EG的功能。结论基于我们的研究结果，这项研究为长期存在的关于力量传递阈值的争论提供了一个协调的解释。另一种新的解释是：EG通过改变剪刀角的中位数和变化范围来调节机械转导，而EG通过控制剪刀角来调节微血管屏障，从而影响细胞间隙。
Aim Endothelial glycocalyx (EG) plays a pivotal role in a plethora of diseases, like cardiovascular and renal diseases. One hallmark function of the EG as a mechanotransducer which transmits mechanical signals into cytoplasm has been documented for decades. However, the basic question - how the glycocalyx transmits the flow shear stress- is unanswered so far. Our aim is to shed light on the fundamental mode of signal transmission from flow to the endothelial cytoskeleton. Methods We conduct a series of large-scale molecular dynamics computational experiments to investigate the dynamics of glycocalyx under varying conditions (changing blood flow velocities and shedding of glycocalyx sugar chains). Results We have identified that the main pathway of signal transmission in this system manifests as a scissors-like motion of the Syndecan-4 core protein. Results have suggested that the force transmitted into the cytoskeleton with an order of 10 similar to 100 pN, and the main function of sugar chains of a glycocalyx element is to protect the core proteins from severe conformational changes thereby maintaining the functionality of the EG. Conclusion This research provides a reconciling explanation for a longstanding debate about the force transmission threshold based on our findings. A new explanation has also been provided to relate the role of the EG as a mechanotransducer to its function as a microvascular barrier: the EG regulates the mechanotransduction by altering the median value and variation range of the scissor angle, and the EG governs the microvascular barrier via controlling the scissor angle which will affect the intercellular cleft.