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Research Papers

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

[+] Author and Article Information
Leonie Rouleau

Department of Chemical Engineering, McGill University, 3610 University, Montreal, QC, H3A 2B2, Canada; Montreal Heart Institute, Canada

Monica Farcas

Department of Chemical Engineering, McGill University, 3610 University, Montreal, QC, H3A 2B2, Canada

Jean-Claude Tardif

Rosaire Mongrain

Montreal Heart Institute, 5000 Bélanger Street, Montreal, QC H1T 1C8, Canada; Department of Mechanical Engineering, McGill University, Montreal, QC, H3A 2B2, Canada

Department of Chemical Engineering, McGill University, 3610 University, Montreal, QC, H3A 2B2, Canada; Montreal Heart Institute, Canadarichard.leask@mcgill.ca

J Biomech Eng 132(8), 081013 (Jul 29, 2010) (10 pages) doi:10.1115/1.4001891 History: Received July 08, 2009; Revised May 26, 2010; Posted May 31, 2010; Published July 29, 2010; Online July 29, 2010

## 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 $τ=4.5 dyn/cm2$, $9 dyn/cm2$, and $18 dyn/cm2$) 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.

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## Figures

Figure 1

(a) Regions of the three dimensional in vitro 50% asymmetric stenosis model, including the inlet, acceleration, deceleration, and outlet regions on the side of the stenosis and positive and negative gradient regions on the opposite side. The morphological parameters were assessed in the different regions, each ∼10 mm length, as indicated by the bar. Flow profiles for a mean entrance Reynolds number of 200 and wall shear stress of 18 dyn/cm2 are shown, which includes a recirculation zone. (b) Schematic of the perfusion flow loop, including individual vented reservoirs and custom built dampeners, a low pulsatility peristaltic pump, and the in vitro models.

Figure 2

Photochromic molecular flow visualization results for both the stenosis side ((a) and (c)) and the opposite side ((b) and (d)) of the model for different Reynolds numbers ranging from 50 to 200 and resulting in a mean entrance wall shear stresses from 4.5 dyn/cm2 to 18 dyn/cm2. The wall shear stress plots ((a) and (b)) are presented along with the values of the wall shear stress gradient ((c) and (d)). On the side of the stenosis, a recirculation zone with flow reversal is created at Re=200 and similar but slightly smoother gradients are present on the opposite site of the stenosis.

Figure 3

Qualitative observation of microscopic images of the cells showed changes in shape and alignment after 24 h upon flow exposure (direction indicated by the arrow) at different wall shear stress magnitude (a). Histogram of the distribution of the angle of orientation is also shown for cells in static conditions (b). Comparison of the straight tubular model with the inlet and outlet regions of the stenosis model for Re=200 at 12 and 24 h (c). The wall shear stress magnitude and duration effects on the shape index in the fully developed regions (inlet and outlet) are shown (d).

Figure 4

Representative images of crystal violet stained endothelial cells on the stenosis side of the model in the inlet, acceleration, deceleration (recirculation) and outlet regions after 24 h of flow exposure at Re=200 (a). Shape index values for each region at Re=200 and different times (b) and at different mean entrance Reynolds number after 24 h of flow (c).

Figure 5

Histograms of the angle of orientation in the different regions of the models (inlet (a), acceleration (b), deceleration (c), and outlet (d)) on the side of the stenosis after 24 h of flow exposure at Re=200

Figure 6

Microscopic images of endothelial cells stained with crystal violet on the opposite side of the stenosis in the inlet, positive and negative wall shear stress gradient and outlet regions after 24 h of flow exposure at Re=200 (a). Corresponding shape index values for each region at Re=200 and different times (b) and at different mean entrance Reynolds number after 24 h of flow (c).

Figure 7

Histograms of the angle of orientation in the different regions of the models (inlet (a), positive gradient (b), negative gradient (c), and outlet (d)) on the opposite side of the stenosis after 24 h of flow exposure at Re=200

Figure 8

F-actin filament distribution at different times and wall shear stress magnitudes as imaged by confocal microscopy (magnification 20×). The changes were progressive and magnitude dependent.

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