Distinct endothelial phenotypes evoked by arterial waveforms derived from atherosclerosis-susceptible and -resistant regions of human vasculature

Abstract

Atherosclerotic lesion localization to regions of disturbed flow within certain arterial geometries, in humans and experimental animals, suggests an important role for local hemodynamic forces in atherogenesis. To explore how endothelial cells (EC) acquire functional͞dysfunctional phenotypes in response to vascular region-specific flow patterns, we have used an in vitro dynamic flow system to accurately reproduce arterial shear stress waveforms on cultured human EC and have examined the effects on EC gene expression by using a high-throughput transcriptional profiling approach. The flow patterns in the carotid artery bifurcations of several normal human subjects were characterized by using 3D flow analysis based on actual vascular geometries and blood flow profiles. Two prototypic arterial waveforms, ''athero-prone'' and ''athero-protective,'' were defined as representative of the wall shear stresses in two distinct regions of the carotid artery (carotid sinus and distal internal carotid artery) that are typically ''susceptible'' or ''resistant,'' respectively, to atherosclerotic lesion development. These two waveforms were applied to cultured EC, and cDNA microarrays were used to analyze the differential patterns of EC gene expression. In addition, the differential effects of atheroprone vs. athero-protective waveforms were further characterized on several parameters of EC structure and function, including actin cytoskeletal organization, expression and localization of junctional proteins, activation of the NF-B transcriptional pathway, and expression of proinflammatory cytokines and adhesion molecules. These global gene expression patterns and functional data reveal a distinct phenotypic modulation in response to the wall shear stresses present in atherosclerosis-susceptible vs. atherosclerosisresistant human arterial geometries.

Neutrophil Adhesion on Endothelial Cells in a Novel Asymmetric Stenosis Model: Effect of Wall Shear Stress Gradients

“…In vivo post-mortem studies have revealed that plaque disruption usually occurs at the shoulders (6,(25)(26)(27), where the cap is often thinnest and most heavily infiltrated with white blood cells including neutrophils and monocytes (28). Inflammatory markers are also differentially expressed in vivo in disturbed flow regions, such as those created by an eccentric stenosis (29,30). It is believed that local hemodynamic factors and mass transport dictate plaque stability and rupture location.…”

“…TNF-α stimulation upregulates the expression of cell adhesion molecules (Figure 2), which are expressed in atheroprone regions and regions presenting plaque (30,38). It thus creates a dysfunctional endothelium, characterized by the expression of pro-inflammatory molecules and other ligands supporting leukocyte adhesion (39).…”

Integrating biological vasculature into a multi-organ-chip microsystem

“…Certain waveforms in humans have been associated with certain disease susceptibility. 24 This implies the further evaluation of the MOC platform for research into such pathological processes of the human cardiovascular system.…”

Design of a cone-and-plate device for controlled realistic shear stress stimulation on endothelial cell monolayers

“…Computational studies on realistic vascular geometries showed that arterial branches and curvature induce blood flow separation and recirculation, and in these areas ECs experience low and/or oscillating (reciprocating) WSS stimuli (Dai et al 2004;Ene-Iordache and Remuzzi 2012;Sui et al 2015). In vivo and in vitro studies correlated reciprocating WSS waveforms with EC dysfunctions caused mainly by altered cell signaling, increased permeability, and impaired vessel remodeling (Chiu and Chien 2011;Davies et al 2013).…”