Hemodynamic Environments from Opposing Sides of Human Aortic Valve Leaflets Evoke Distinct Endothelial Phenotypes In Vitro

Hemodynamic Environments from Opposing Sides of Human Aortic Valve Leaflets Evoke Distinct Endothelial Phenotypes In Vitro

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Hemodynamic Environments from Opposing Sides of Human Aortic Valve Leaflets Evoke Distinct Endothelial Phenotypes In Vitro

dc.contributor.author	Weinberg, Eli J.
dc.contributor.author	Mack, Peter J.
dc.contributor.author	García-Cardeña, Guillermo
dc.contributor.author	Kaazempur Mofrad, Mohammad R.
dc.contributor.author	Schoen, Frederick Jack
dc.date.accessioned	2010-12-21T18:29:08Z
dc.date.issued	2010
dc.identifier.citation	Weinberg, Eli J., Peter J. Mack, Frederick J. Schoen, Guillermo García-Cardeña, and Mohammad R. Kaazempur Mofrad. 2010. Hemodynamic environments from opposing sides of human aortic valve leaflets evoke distinct endothelial phenotypes in vitro. Cardiovascular Engineering 10(1): 5-11.	en_US
dc.identifier.issn	1567-8822	en_US
dc.identifier.uri	http://nrs.harvard.edu/urn-3:HUL.InstRepos:4632589
dc.description.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.	en_US
dc.language.iso	en_US	en_US
dc.publisher	Springer US	en_US
dc.relation.isversionof	doi:10.1007/s10558-009-9089-9	en_US
dc.relation.hasversion	http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2837826/pdf/	en_US
dash.license	LAA
dc.subject	aortic valve	en_US
dc.subject	calcific aortic stenosis	en_US
dc.subject	endothelial mechanotransduction	en_US
dc.subject	shear stress	en_US
dc.subject	cell mechanics and mechanotransduction	en_US
dc.subject	valvular disease	en_US
dc.title	Hemodynamic Environments from Opposing Sides of Human Aortic Valve Leaflets Evoke Distinct Endothelial Phenotypes In Vitro	en_US
dc.type	Journal Article	en_US
dc.description.version	Version of Record	en_US
dc.relation.journal	Cardiovascular Engineering	en_US
dash.depositing.author	Schoen, Frederick Jack
dc.date.available	2010-12-21T18:29:08Z
dash.affiliation.other	HMS^Health Sciences and Technology	en_US
dash.affiliation.other	HMS^Pathology	en_US