[HTML][HTML] Hemodynamic environments from opposing sides of human aortic valve leaflets evoke distinct endothelial phenotypes in vitro

EJ Weinberg, PJ Mack, FJ Schoen… - Cardiovascular …, 2010 - Springer
EJ Weinberg, PJ Mack, FJ Schoen, G García-Cardeña, MR Kaazempur Mofrad
Cardiovascular engineering, 2010Springer
The regulation of valvular endothelial phenotypes by the hemodynamic environments of the
human aortic valve is poorly understood. The nodular lesions of calcific aortic stenosis
(CAS) develop predominantly beneath the aortic surface of the valve leaflets in the valvular
fibrosa layer. However, the mechanisms of this regional localization remain poorly
characterized. In this study, we combine numerical simulation with in vitro experimentation to
investigate the hypothesis that the previously documented differences between valve …
Abstract
The regulation of valvular endothelial phenotypes by the hemodynamic environments of the human aortic valve is poorly understood. The nodular lesions of calcific aortic stenosis (CAS) develop predominantly beneath the aortic surface of the valve leaflets in the valvular fibrosa layer. However, the mechanisms of this regional localization remain poorly characterized. In this study, we combine numerical simulation with in vitro experimentation to investigate the hypothesis that the previously documented differences between valve endothelial phenotypes are linked to distinct hemodynamic environments characteristic of these individual anatomical locations. A finite-element model of the aortic valve was created, describing the dynamic motion of the valve cusps and blood in the valve throughout the cardiac cycle. A fluid mesh with high resolution on the fluid boundary was used to allow accurate computation of the wall shear stresses. This model was used to compute two distinct shear stress waveforms, one for the ventricular surface and one for the aortic surface. These waveforms were then applied experimentally to cultured human endothelial cells and the expression of several pathophysiological relevant genes was assessed. Compared to endothelial cells subjected to shear stress waveforms representative of the aortic face, the endothelial cells subjected to the ventricular waveform showed significantly increased expression of the “atheroprotective” transcription factor Kruppel-like factor 2 (KLF2) and the matricellular protein Nephroblastoma overexpressed (NOV), and suppressed expression of chemokine Monocyte-chemotactic protein-1 (MCP-1). Our observations suggest that the difference in shear stress waveforms between the two sides of the aortic valve leaflet may contribute to the documented differential side-specific gene expression, and may be relevant for the development and progression of CAS and the potential role of endothelial mechanotransduction in this disease.
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