Abstract
Exposure of endothelial cells to low and multidirectional blood flow is known to promote a pro-atherogenic phenotype. The mechanics of the vessel wall is another important mechano-stimulus within the endothelial cell environment, but no study has examined whether changes in the magnitude and direction of cell stretch can be pro-atherogenic. Herein, we developed a custom cell stretching device to replicate the in vivo stretch environment of the endothelial cell and examined whether low and multidirectional stretch promote nuclear translocation of NF-κB. A fluid–structure interaction model of the device demonstrated a nearly uniform strain within the region of cell attachment and a negligible magnitude of shear stress due to cyclical stretching of the cells in media. Compared to normal cyclical stretch, a low magnitude of cyclical stretch or no stretch caused increased expression of nuclear NF-κB (p = 0.09 and p < 0.001, respectively). Multidirectional stretch also promoted significant nuclear NF-κB expression, comparable to the no stretch condition, which was statistically higher than the low (p < 0.001) and normal (p < 0.001) stretch conditions. This is the first study to show that stretch conditions analogous to atherogenic blood flow profiles can similarly promote a pro-atherogenic endothelial cell phenotype, which supports a role for disturbed vessel wall mechanics as a pathological cell stimulus in the development of advanced atherosclerotic plaques.
Highlights
Coronary artery disease is the worldwide leading cause of death.[27]
The fluid–structure interaction (FSI) model showed that the shear stress imposed onto the cells as the membrane is cyclically stretched at 1 Hz while immersed in media is a maximum of 0.006 Pa, which is far below physiological values of approximately 1.5 Pa and negligible in this system
Each of these two disturbed stretch conditions was motivated by an analogous atherogenic flow profile, low flow and multidirectional flow, which suggests that disturbed vessel wall stretch can be atherogenic similar to disturbed flow
Summary
Coronary artery disease is the worldwide leading cause of death.[27]. It is characterized as a chronic lipiddriven inflammatory disease that manifests as atherosclerotic plaques composed of a lipid-rich necrotic core and immune cells within the intima of the coronary arteries.[11,27] Plaque development requires a dysfunctional endothelium (the normal endothelium regulates the passage of proteins and cells from the bloodstream into the vessel wall) that results in expression of pro-inflammatory mediators such as NFjB, disruption of cell–cell junctions, and expression of leukocyte adhesion molecules (e.g., vascular cell adhesion molecule-1). The precise environmental cues that promote a dysfunctional endothelium are not well characterized, but the tissue mechanical environment is known to play an important role.[11,26]. Studies related to atherosclerosis have demonstrated that chronic levels of low shear stress and variations in shear stress direction over the cardiac cycle, called multidirectional shear stress, both promote the expression of numerous atherogenic signaling molecules, including NF-jB, within endothelial cells leading to a dysfunctional phenotype.[11,22,34] As a result, atherosclerotic plaques tend to localize to regions of the vasculature that experience these flow disturbances, such as within the inner curvature of arteries[29] or near bifurcations.[18] More recent studies have shown that introducing these flow disturbances within the arteries of hypercholesterolemic animals can induce the development of advanced atherosclerotic plaques.[7,27]
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