Regulation of the endothelial cell glycocalyx and its role in mechanotransduction
Abstract
Atherosclerosis is an inflammatory disease of the endothelium which is focally concentrated to regions of complex blood flow in the vasculature. Flow fields created in different vascular geometries, such as curvature and bifurcations, result in spatial wall shear stress gradients (WSSGs) which have been found to cause an inflammatory phenotype in endothelial cells (ECs). ECs sense these forces and elicit a biochemical response, a process termed mechanotransduction. Although the specific pathways are still unclear, a dynamic cell-surface proteoglycan layer called the glycocalyx is hypothesized to play a significant role in EC mechanotransduction. The work in this thesis investigates the regulation of the glycocalyx in regions of WSSGs to better define its role in mechanotransduction. Heparan sulphate, a major component of the glycocalyx, was chosen as a target for degradation to impair the function of the glycocalyx and quantify shedding of the structure. In vitro cell culture models mimicking physiologically relevant regions of curvature and vessel stenosis were used in flow experiments to determine their relation to EC health. It was found that in both geometries, WSSGs resulted in an inflammatory EC response including cellular rounding and increased leukocyte adhesion. Enzymatic degradation of heparan sulphate attenuated the morphological response and adhesion patterns in these regions, demonstrating the role of the glycocalyx as a mechanotransducer. In these regions,…
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Evidence Hub reads this as a thesis, done in cell cultures (in vitro), not in people. Its evidence level is 5 of 5 (Very low · case / narrative / animal / in vitro / in silico). Case reports, narrative reviews, and animal, cell or computer-model studies give the weakest evidence for human health.
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