Mechanotransmission of haemodynamic forces by the endothelial glycocalyx in a full-scale arterial model

The glycocalyx has been identified as a key mechanosensor of the shear forces exerted by the streaming blood onto the vascular endothelial lining. Although the biochemical reaction to the blood flow has been extensively studied, the mechanism of transmission of the hemodynamic shear forces to the endothelial transmembrane anchoring structures and, consequently, to the subcellular elements in the cytoskeleton, is still not fully understood. Here we apply a multiscale approach to elucidate how hemodynamic shear forces are transmitted to the transmembrane anchors of endothelial cells. Wall shear stress time histories, as obtained from image-based computational hemodynamics models of a carotid bifurcation, are used as a load and a continuum model is applied to obtain the mechanical response of the glycocalyx all along the cardiac cycle. The main findings of this in silico study are that: (1) the forces transmitted to the transmembrane anchors are in the range of 1-10 pN, which is in the order of magnitude reported for the different conformational states of transmembrane mechanotranductors; (2) locally, the forces transmitted to the anchors of the glycocalyx structure can be markedly different from the near-wall hemodynamic shear forces both in amplitude and frequency content. Despite the continuum assumption adopted in this study, the findings of this in silico approach warrant future studies focusing on the actual forces transmitted to the transmembrane mechanotrasductors, which might outperform hemodynamic descriptors of disturbed shear as localizing factors of vascular disease.

糖萼（glycocalyx）已被证实是流动血液作用于血管内皮层的剪切力的关键机械感受器。尽管学界已对血流引发的生化反应开展了大量研究，但血流动力学剪切力向内皮细胞跨膜锚定结构，进而向细胞骨架内亚细胞组分传递的具体机制，仍未完全阐明。本研究采用多尺度方法，旨在阐明血流动力学剪切力如何传递至内皮细胞的跨膜锚点。本研究从颈动脉分叉的基于图像的计算血流动力学模型中提取壁面切应力（wall shear stress）时程曲线作为载荷，并采用连续介质模型，以获取整个心动周期内糖萼的力学响应。本计算机模拟（in silico）研究的主要发现如下：(1) 传递至跨膜锚点的力大小介于1~10皮牛（pN）之间，这一量级与跨膜机械转导蛋白（transmembrane mechanotransducers）不同构象状态下的报道值相符；(2) 在局部区域，传递至糖萼结构锚点的力在幅值和频率特征上，均可与近壁血流动力学剪切力存在显著差异。尽管本研究采用了连续介质假设，但该计算机模拟方法的发现表明，未来有必要针对传递至跨膜机械转导蛋白的实际力开展研究——这类实际力作为血管疾病的定位因子，可能比扰动剪切的血流动力学指标更具优势。