Abstract
Hemodynamic forces play an important role in the non-uniform distribution of atherosclerotic lesions. Endothelial cells are exposed simultaneously to fluid wall shear stress (WSS) and solid circumferential stress (CS). Due to variations in impedance (global factors) and geometric complexities (local factors) in the arterial circulation a time lag arises between these two forces that can be characterized by the temporal phase angle between CS and WSS (stress phase angle–SPA). Asynchronous flows (SPA close to -180°) that are most prominent in coronary arteries have been associated with localization of atherosclerosis. Reversing oscillatory flows characterized by an oscillatory shear index (OSI) that is great than zero are also associated with atherosclerosis localization. In this study we examined the relationship between asynchronous flows and reversing flows in altering the expression of 37 genes relevant to atherosclerosis development. In the case of reversing oscillatory flow, we observed that the asynchronous condition upregulated 8 genes compared to synchronous hemodynamics, most of them proatherogenic. Upregulation of the pro-inflammatory transcription factor NFκB p65 was confirmed by western blot, and nuclear translocation of NFκB p65 was confirmed by immunofluorescence staining. A comparative study between non-reversing flow and reversing flow found that in the case of synchronous hemodynamics, reversing flow altered the expression of 11 genes, while in the case of asynchronous hemodynamics, reversing flow altered the expression of 17 genes. Reversing flow significantly upregulated protein expression of NFκB p65 for both synchronous and asynchronous conditions. Nuclear translocation of NFκB p65 was confirmed for synchronous and asynchronous conditions in the presence of flow reversal. These data suggest that asynchronous hemodynamics and reversing flow can elicit proatherogenic responses in endothelial cells compared to synchronous hemodynamics without shear stress reversal, indicating that SPA as well as reversal flow (OSI) are important parameters characterizing arterial susceptibility to disease.
Highlights
Hemodynamic forces play a key role in the localization of atherosclerosis
Nuclear translocation of NFκB p65 was confirmed for synchronous and asynchronous conditions in the presence of flow reversal. These data suggest that asynchronous hemodynamics and reversing flow can elicit proatherogenic responses in endothelial cells compared to synchronous hemodynamics without shear stress reversal, indicating that Stress Phase Angle” (SPA) as well as reversal flow (OSI) are important parameters characterizing arterial susceptibility to disease
First we examined gene expression of 38 atherosclerosis-related genes under synchronous hemodynamics with reversal flow–denoted SPA = 0 ̊R (OSI = 0.15), and asynchronous hemodynamics with reversal flow–denoted SPA = -180 ̊R (OSI = 0.15) to see if changes in SPA are influential when there is flow reversal
Summary
Hemodynamic forces play a key role in the localization of atherosclerosis. Endothelial cells (ECs) lining the blood vessels are exposed simultaneously to wall shear stress (WSS) caused by pulsatile blood flow and circumferential stress/strain (CS) caused by the distension of the wall diameter in response to the pressure pulse. The introduction of laser Doppler and ultrasound velocimetry facilitated more precise measurements of local hemodynamics and the characterization of flow reversal. Qiu and Tarbell showed that due to distal impedance in the circulation (global factors) and the non-linear inertia of blood flow in complex geometries (local factors), a time (phase) lag arises between the pulsatile WSS and CS. This phase lag was characterized by the temporal phase angle between CS and WSS (φ[CS]– φ[WSS]) that has been called the “Stress Phase Angle” (SPA) [4, 5]
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