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

Abstract

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 ~ 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.

Extended disorder at the cell surface: The conformational landscape of the ectodomains of syndecans

“…However, they are able to form α-helices in presence of trifluoroethanol. This is in agreement with the partial folding into α-helix of the ectodomain of syndecan-4 during molecular dynamic simulations carried out at the glycocalyx level [47] .…”

Syndecan‐4, a model proteoglycan to study endothelial glycocalyx mechanosensing and signal transduction

“…In conclusion, in accordance with previous studies are the calculations by Jiang et al of the uncovered transmitted force in the order of 10‐100pN and the presence of a threshold in GAG reduction and changes in mechanotransduction. Together with earlier calculations this could mean that syndecan‐4 transduces force only at a certain threshold of shear stress to which endothelial cells will respond.…”

“…According to the same published model, assuming the endothelial glycocalyx as a rigid body in which the torque of the whole layer was studied, cytoskeletal deformation would be inhibited only when all sugar chains of the glycocalyx were removed, although other experiments suggest a threshold in which about 30%‐45% reduction already would inhibit cytoskeletal reorganization. Reconciling these differences, the soft matter model proposed in this study shows that flexibility of the linkage between the ecto‐ and transmembrane subdomains of the core protein allows that forces can only partly be transmitted into the cytoskeleton. Thus by only removing 16.7% of the sugar chains, in terms of scissors angular variation, result already in a reduction of 55% in mechanotransduction.…”

“…In the present issue of Acta Physiologica , Jiang, et al tested how the endothelial glycocalyx transmits the blood flow shear stress to the cytoskeleton. In a series of large‐scale molecular dynamics computational experiments the dynamics of the proteoglycan syndecan‐4 force transmission is examined under varying conditions, that is, blood flow velocity changes and proteoglycan sugar chain shedding.…”

Understanding the Role of Endothelial Glycocalyx in Mechanotransduction via Computational Simulation: A Mini Review

“…In the classic vasoregulation signalling problem -in what manner does glycocalyx transmit force to the cytoskeleton from the flowing blood?, the glycocalyx was regarded as a rigid body and the force was transmitted by the local torque induced by the movement of the glycocalyx core protein. In recent MD simulations, Jiang et al (2020b) elucidated the dynamics of Syndecan-4 (a typical type of transmembrane protein of the glycocalyx), and concluded that a scissor-like motion of the Syndecan-4 transmembrane dimer, together with its bending, is responsible for the force transmission and the force transmitted into the cytoplasm is of an order 10-100 pN. The MD model and force transmission mode is summarised in Figure 2.…”