PDF(Pubmed)
Abstract：
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.
摘要：
血管的内层，内皮，是由内皮细胞组成的.血管内皮(VE)-钙粘蛋白蛋白与来自相邻细胞的VE-钙粘蛋白形成键,以确定细胞之间的间隙的大小,从而调节可以穿过内皮的颗粒的大小。化学线索，如凝血酶，已知细胞和细胞外基质(ECM)的机械性质影响内皮细胞的通透性。在患有包括心血管疾病在内的疾病的患者中发现异常的渗透性，癌症,和COVID-19。尽管对影响内皮通透性的一些调节机制进行了充分的研究,一些机械和化学刺激如何同时影响内皮通透性的细节尚不清楚.在这篇文章中,我们提出了一个连续级的机械建模框架来研究VE-钙粘素键的高度动态性质。从VE-cadherin复合物已知表现出的抓滑行为中获得灵感，我们将VE-cadherin亲合键建模为粘性接触，并遵循牵引分离定律。我们明确地对肌动蛋白细胞骨架进行建模，和基质来研究它们在渗透性中的作用。我们的研究表明，机械化学耦合对于模拟基材的机械性能对渗透率的影响是必要的。模拟表明，细胞之间的剪切是双细胞和三细胞连接之间通透性变化的原因，解释实验中观察到的表型差异。由于内皮细胞经历的流动紊乱，牵引力的大小增加导致通透性增加，发现对较硬的ECM的影响更大。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率。因此，我们提出了一个基于接触力学的机械化学模型，以研究由于多种载荷同时作用而引起的内皮单层通透性的变化。
