Endothelial Cell Morphologic Response to Asymmetric Stenosis Hemodynamics: Effects of Spatial Wall Shear Stress Gradients

Abstract

Endothelial cells are known to respond to hemodynamic forces. Their phenotype has been suggested to differ between atheroprone and atheroprotective regions of the vasculature, which are characterized by the local hemodynamic environment. Once an atherosclerotic plaque has formed in a vessel, the obstruction creates complex spatial gradients in wall shear stress. Endothelial cell response to wall shear stress may be linked to the stability of coronary plaques. Unfortunately, in vitro studies of the endothelial cell involvement in plaque stability have been limited by unrealistic and simplified geometries, which cannot reproduce accurately the hemodynamics created by a coronary stenosis. Hence, in an attempt to better replicate the spatial wall shear stress gradient patterns in an atherosclerotic region, a three dimensional asymmetric stenosis model was created. Human abdominal aortic endothelial cells were exposed to steady flow (Re=50, 100, and 200 and tau=4.5 dyn/cm(2), 9 dyn/cm(2), and 18 dyn/cm(2)) in idealized 50% asymmetric stenosis and straight/tubular in vitro models. Local morphological changes that occur due to magnitude, duration, and spatial gradients were quantified to identify differences in cell response. In the one dimensional flow regions, where flow is fully developed and uniform wall shear stress is observed, cells aligned in flow direction and had a spindlelike shape when compared with static controls. Morphological changes were progressive and a function of time and magnitude in these regions. Cells were more randomly oriented and had a more cobblestone shape in regions of spatial wall shear stress gradients. These regions were present, both proximal and distal, at the stenosis and on the wall opposite to the stenosis. The response of endothelial cells to spatial wall shear stress gradients both in regions of acceleration and deceleration and without flow recirculation has not been previously reported. This study shows the dependence of endothelial cell morphology on spatial wall shear stress gradients and demonstrates that care must be taken to account for altered phenotype due to geometric features. These results may help explain plaque stability, as cells in shoulder regions near an atherosclerotic plaque had a cobblestone morphology indicating that they may be more permeable to subendothelial transport and express prothrombotic factors, which would increase the risk of atherothrombosis.

Pulsatile Atheroprone Shear Stress Affects the Expression of Transient Receptor Potential Channels in Human Endothelial Cells

“…16,[20][21][22] Morphological changes represent a late response of endothelial cells on flow exposure. 23 The experiments performed confirmed typical morphological changes of human endothelial cells under the influence of atheroprotective shear stress 24 versus atheroprone 25 and static …”

Multiplexed Fluid Flow Device to Study Cellular Response to Tunable Shear Stress Gradients

“…3,7,8,27,36 Converging–diverging width and T-junction channels have been used to study EC response to WSSGs. 9,15,20,29–31,34,38 Additional studies have used microfluidic techniques for imposing controllable WSSs. 21 These studies have each provided insight into EC response to spatially or temporally varying WSS.…”

Flow reversal promotes intimal thickening in vein grafts

“…15–18 In particular, flow reversal and the accompanying wall shear stress gradient alter endothelial morphology, 19 disrupt normal endothelial barrier function, 20 promote monocyte deposition, 21 induce thrombus formation, 22 and promote gene expression favoring vascular lesion development. 23, 24 In combination, these changes have been shown to enhance lesion development in both clinical 25 and animal-based 26 investigations.…”