Understanding endothelial glycocalyx function under flow shear stress from a molecular perspective

Abstract

BACKGROUND: The endothelial glycocalyx plays a pivotal role in regulating blood flow, filtering blood components, sensing and transducing mechanical signals. These functions are intimately related to its dynamics at the molecular level. OBJECTIVE: The objective of this research is to establish the relationship between the functions of the endothelial glycocalyx and its dynamics at the molecular level. METHODS: To establish such a relationship, large-scale molecular dynamics simulations were undertaken to mimic the dynamics of the glycocalyx and its components in the presence of flow shear stresses. RESULTS: First, motions of the glycocalyx core protein and the pertinent subdomains were scrutinised. Threedirectional movements of the glycocalyx core protein were observed, although the flow was imposed only in the x direction. Such an observation contributes to understanding the glycocalyx redistribution as reported in experiments. Unsynchronised motion of the core protein subdomains was also spotted, which provides an alternative explanation of macroscopic phenomena. Moreover, the dynamics, rootmean-square-deviations and conformational changes of the sugar chains were investigated. Based on the findings, an alternative force transmission pathway, the role of sugar chains, and potential influence on signalling transduction pathway were proposed and discussed. CONCLUSIONS: This study relates the functions of the glycocalyx with its microscopic dynamics, which fills a knowledge gap about the links between different scales.

Principal mode of Syndecan‐4 mechanotransduction for the endothelial glycocalyx is a scissor‐like dimer motion

“…According to our in silico experiments, only by removing 16.7% of the sugar chains (3 of 18 sugar chains are removed in case II), the mechanotransduction in terms of scissor angular variation ranges has been dramatically reduced by 55%, which validates the existence of the proposed threshold. It is noteworthy that case III indeed indicates another force transmission pathway that flow shear stress is directly transmitted via the core protein, especially in the situation with a bulk of sugar chains removed, and the alternative force transmission pathway was discussed in our previous studies …”

“…It is noteworthy that case III indeed indicates another force transmission pathway that flow shear stress is directly transmitted via the core protein, especially in the situation with a bulk of sugar chains removed, and the alternative force transmission pathway was discussed in our previous studies. 25,30…”

“…With the advent of the detailed structures and the implementation of supercomputers, a series of interesting phenomena regarding the EG layer have been discovered, and most of these findings are from our group. For example, the blood flow alters the conformation of the EG; the conformational changes then affect their interactions with the surrounding ions, modifying the microvascular ion transport properties . However, these studies mainly focus on atomic/molecular events occurring in the ectodomain.…”

“…For example, the blood flow alters the conformation of the EG [25][26][27][28] ; the conformational changes then affect their interactions with the surrounding ions, modifying the microvascular ion transport properties. [29][30][31] However, these studies mainly focus on atomic/molecular events occurring in the ectodomain. The mechanism for the EG implementing its transmembrane functionality (mechanotransduction) remains undeciphered.…”

Glycocalyx Sensing with a Mathematical Model of Acoustic Shear Wave Biosensor

“…In [ 5 ], e.g., GL is modeled as a medium of variable and adaptive porosity. Some other works (see, e.g., [ 6 ]) use molecular dynamic simulation methods to mimic the dynamics of the GL and its components. In [ 7 ], the endothelial cells are modeled as a nearly incompressible hyperelastic neo-Hookean material.…”