A mechanical modelling framework to study endothelial permeability
A mechanical modelling framework to study endothelial permeability
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研究内皮渗透性的机械建模框架
DOI：
10.1101/2023.07.28.551049
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Keshavanarayana P
中科院分区：
文献类型：
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作者：
Keshavanarayana P
血管的内层，即内皮，由内皮细胞组成。血管内皮 (VE)-钙粘蛋白与邻近细胞的 VE-钙粘蛋白形成键，以确定细胞之间间隙的大小，从而调节可以穿过内皮的颗粒的大小。已知凝血酶等化学信号以及细胞和细胞外基质的机械特性会影响内皮细胞的通透性。患有心血管疾病、癌症和 COVID-19 等疾病的患者会发现渗透性异常。尽管影响内皮通透性的一些调节机制已得到充分研究，但同时作用的几种机械和化学刺激如何影响内皮通透性的细节尚不清楚。在本文中，我们提出了一个连续体级机械建模框架来研究 VE-钙粘蛋白键的高度动态性质。受 VE-钙粘蛋白复合物已知表现出的抓滑行为的启发，我们将 VE-钙粘蛋白同亲键建模为遵循牵引分离定律的与损伤的内聚接触。我们明确模拟肌动蛋白细胞骨架和底物以研究它们在通透性中的作用。我们的研究表明，机械化学耦合对于模拟基材机械性能对渗透性的影响是必要的。模拟表明，细胞之间的剪切力导致双细胞和三细胞连接之间的渗透性变化，这解释了实验中观察到的表型差异。由于内皮细胞经历的流动紊乱而导致牵引力大小的增加，导致渗透性增加，并且发现对于较硬的细胞外基质，效果更大。最后，我们表明，在不受约束的情况下，圆柱形单层比平面单层表现出更高的渗透性。因此，我们提出了一种基于接触力学的机械化学模型来研究由于同时作用的多个载荷而导致的内皮单层渗透性的变化。
The inner lining of blood vessels, the endothelium, is made up of endothelial cells. Vascular endothelial (VE)-cadherin protein forms a bond with VE-cadherin from neighboring cells to determine the size of gaps between the cells and thereby regulate the size of particles that can cross the endothelium. Chemical cues such as thrombin, along with mechanical properties of the cell and extracellular matrix are known to affect the permeability of endothelial cells. Abnormal permeability is found in patients suffering from diseases including cardiovascular diseases, cancer, and COVID-19. Even though some of the regulatory mechanisms affecting endothelial permeability are well studied, details of how several mechanical and chemical stimuli acting simultaneously affect endothelial permeability are not yet understood. In this article, we present a continuum-level mechanical modeling framework to study the highly dynamic nature of the VE-cadherin bonds. Taking inspiration from the catch-slip behavior that VE-cadherin complexes are known to exhibit, we model the VE-cadherin homophilic bond as cohesive contact with damage following a traction-separation law. We explicitly model the actin cytoskeleton and substrate to study their role in permeability. Our studies show that mechanochemical coupling is necessary to simulate the influence of the mechanical properties of the substrate on permeability. Simulations show that shear between cells is responsible for the variation in permeability between bicellular and tricellular junctions, explaining the phenotypic differences observed in experiments. An increase in the magnitude of traction force due to disturbed flow that endothelial cells experience results in increased permeability, and it is found that the effect is higher on stiffer extracellular matrix. Finally, we show that the cylindrical monolayer exhibits higher permeability than the planar monolayer under unconstrained cases. Thus, we present a contact mechanics-based mechanochemical model to investigate the variation in the permeability of endothelial monolayer due to multiple loads acting simultaneously.
影响因子：
4.2
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