Research Papers

Vascular Cell Adhesion Molecule-1 Expression in Endothelial Cells Exposed to Physiological Coronary Wall Shear Stresses

[+] Author and Article Information
Lucy M. O'Keeffe, Anna V. Piterina, Tim McGloughlin

Centre for Applied Biomedical Engineering Research, Materials and Surface Science Institute, University of Limerick, Castletroy, Limerick, Ireland

Gordon Muir

 Institute of Technology, Sligo, Ireland

J Biomech Eng 131(8), 081003 (Jun 19, 2009) (9 pages) doi:10.1115/1.3148191 History: Received October 09, 2007; Revised April 22, 2009; Published June 19, 2009

Atherosclerosis is consistently found in bifurcations and curved segments of the circulatory system, indicating disturbed hemodynamics may participate in disease development. In vivo and in vitro studies have shown that endothelial cells (ECs) alter their gene expression in response to their hemodynamic environment, in a manner that is highly dependent on the exact nature of the applied forces. This research exposes cultured ECs to flow patterns present in the coronary arterial network, in order to determine the role of hemodynamic forces in plaque initiation. Vascular cell adhesion molecule-1 (VCAM-1) was examined as an indicator of plaque growth, as it participates in monocyte adhesion, which is one of the initial steps in the formation of fatty lesions. The hemodynamics of a healthy right and left coronary artery were determined by reconstructing 3D models from cineangiograms and employing computational fluid dynamic models to establish physiological coronary flow patterns. Wall shear stress (WSS) profiles selected from these studies were applied to ECs in a cone and plate bioreactor. The cone and plate system was specifically designed to be capable of reproducing the high frequency harmonics present in physiological waveforms. The shear stresses chosen represent those from regions prone to disease development and healthier arterial segments. The levels of the transcriptional and cell surface anchored VCAM-1 were quantified by flow cytometry and real time RT-PCR over a number of timepoints to obtain a complete picture of the relationship between this adhesion molecule and the applied shear stress. The WSS profiles from regions consistently displaying a higher incidence of plaques in vivo, induced greater levels of VCAM-1, particularly at the earlier timepoints. Conversely, the WSS profile from a straight section of vessel with undisturbed flow indicated no upregulation in VCAM-1 and a significant downregulation after 24 h, when compared with static controls. Low shear stress from the outer wall of a bifurcation induced four times the levels of VCAM-1 messenger ribonucleic acid (mRNA) after four hours when compared with levels of mRNA induced by WSS from a straight arterial section. This shear profile also induced prolonged expression of the surface protein of this molecule. The current study has provided insight into the possible influences of coronary hemodynamics on plaque localization, with VCAM-1 only significantly induced by the WSS from disease prone regions.

Copyright © 2009 by American Society of Mechanical Engineers
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Figure 1

The cone and plate bioreactor

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Figure 2

WSS profiles selected from the RCA for the in vitro studies

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Figure 3

WSS profile from the outer wall of the LAD bifurcation

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Figure 4

VCAM-1 levels in ECs exposed to the Outer Bifurcation WSS profile when normalized to static controls (n=3; ∗=p<0.05, ∗∗=p<0.01, ∗∗∗=p<0.001)

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Figure 5

VCAM-1 levels in ECs exposed to the inner curvature WSS profile when normalized to static controls (n=3; ∗=p<0.05, ∗∗=p<0.01, ∗∗∗=p<0.001)

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Figure 6

VCAM-1 levels in ECs exposed to the straight WSS profile when normalized to static controls (n=3; ∗=p<0.05, ∗∗=p<0.01, ∗∗∗=p<0.001)

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Figure 7

VCAM-1 mRNA expression as a function of the time-averaged magnitude of the applied WSS

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Figure 8

VCAM-1 mRNA expression as a function of the peak temporal gradient and OSI of the applied shear stress




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