Abstract
Wall shear stress gradients (WSSGs) induce an inflammatory phenotype in endothelial cells (ECs) which is hypothesized to be mediated by mechanotransduction through the EC glycocalyx (GCX). We used a three-dimensional in vitro cell culture model with a 180o curved geometry to investigate if WSSGs created by curvature can cause EC inflammation and disruption of the GCX. The hydrodynamics of the model elicited a morphological response in ECs as well as a pattern of leukocyte adhesion towards the inner wall of curvature that was attenuated with enzymatic removal of GCX components. GCX degradation was also observed in regions of curvature which corresponded to increased activity of MMPs. Together, these results support the hypothesis that the EC GCX is involved in mechanotransduction of WSSGs and that components of the GCX are regulated by MMP activity in regions of curvature.
Highlights
The localization of atherosclerosis to regions of disturbed flow is hypothesized to be caused by endothelial cell (EC) dysfunction in response to the wall shear stress (WSS) patterns in these areas [1]
ECs are sensitive to WSS and are known to exhibit an anti-inflammatory phenotype in response to steady, uniform WSS and a pro-inflammatory phenotype, including cellular rounding and increased leukocyte adhesion, when exposed to wall shear stress gradients (WSSGs) [2,3,4,5,6]
This profile was used to section the model into 3 regions where distinct WSS patterns were observed
Summary
The localization of atherosclerosis to regions of disturbed flow is hypothesized to be caused by endothelial cell (EC) dysfunction in response to the wall shear stress (WSS) patterns in these areas [1]. The GCX extends 0.5–4.5μm into the vessel in vivo [10,11,12] and is comprised of a variety of components including glycocsaminoglycans of which heparan sulfate (HS) is the most abundant [13]. It is a dynamic structure [14] whose disruption has been linked to atherosclerosis and diabetes [15,16,17]. Shedding of GCX components has been linked to matrix metalloproteinases (MMPs) expression and activity, which has been documented to increase in regions of complex flow both in vivo [18] and in vitro [19]
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