Abstract
Endothelial cells lining the walls of blood vessels are exposed simultaneously to wall shear stress (WSS) and circumferential stress (CS) that can be characterized by the temporal phase angle between WSS and CS (stress phase angle – SPA). Regions of the circulation with highly asynchronous hemodynamics (SPA close to -180°) such as coronary arteries are associated with the development of pathological conditions such as atherosclerosis and intimal hyperplasia whereas more synchronous regions (SPA closer to 0°) are spared of disease. The present study evaluates endothelial cell gene expression of 42 atherosclerosis-related genes under asynchronous hemodynamics (SPA=-180 °) and synchronous hemodynamics (SPA=0 °). This study used a novel bioreactor to investigate the cellular response of bovine aortic endothelial cells (BAECS) exposed to a combination of pulsatile WSS and CS at SPA=0 or SPA=-180. Using a PCR array of 42 genes, we determined that BAECS exposed to non-reversing sinusoidal WSS (10±10 dyne/cm2) and CS (4 ± 4 %) over a 7 hour testing period displayed 17 genes that were up regulated by SPA = -180 °, most of them pro-atherogenic, including NFκB and other NFκB target genes. The up regulation of NFκB p50/p105 and p65 by SPA =-180° was confirmed by Western blots and immunofluorescence staining demonstrating the nuclear translocation of NFκB p50/p105 and p65. These data suggest that asynchronous hemodynamics (SPA=-180 °) can elicit proatherogenic responses in endothelial cells compared to synchronous hemodynamics without shear stress reversal, indicating that SPA may be an important parameter characterizing arterial susceptibility to disease.
Highlights
The fluid wall shear stress (WSS) driven by pulsatile blood flow and the solid circumferential stress (CS) driven by pulsatile blood pressure and associated strain, act simultaneously on endothelial cells (EC) lining blood vessels modulating their biological activity
bovine aortic endothelial cells (BAEC) were exposed to WSS (10±10 dyn/cm2) and CS (4 ± 4) for 7 h in the hemodynamic simulator
These results indicate that the device can be used to apply WSS and CS to endothelial cells without causing cell damage
Summary
The fluid wall shear stress (WSS) driven by pulsatile blood flow and the solid circumferential stress (CS) driven by pulsatile blood pressure and associated strain, act simultaneously on endothelial cells (EC) lining blood vessels modulating their biological activity. Recent computational and theoretical studies of SPA have been carried out for a coronary artery [2], the carotid bifurcation [3], end-to-end anastomosis [4], and the EC plasma membrane [5], showing that large negative SPA occurs in regions of the circulation where atherosclerosis and intimal hyperplasia are localized In support of these findings, in vivo studies showed that coronary arteries with highly asynchronous hemodynamics exhibited a pathological gene expression pattern for a limited number of genes [6] and that intimal hyperplasia does not correlate with WSS alone in coronary arteries [7]. These observations suggest that hemodynamic factors other than WSS may play a critical role in localization and development of atherosclerosis
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