Spatial phenotyping of the endocardial endothelium as a function of intracardiac hemodynamic shear stress

JOURNAL OF BIOMECHANICS

卷:50

Article; Proceedings Paper

McCormick, Margaret E.^1,2  Manduchi, Elisabetta^3,4  Witschey, Walter R. T.⁵  Gorman, Robert C.⁶  Gorman, Joseph H., III⁶  Jiang, Yi-Zhou^1,2  Stoeckert, Christian J., Jr.^3,4,7  Barker, Alex J.⁸  Yoon, Samuel¹  Markl, Michael^8,9  Davies, Peter F.^1,2 

[1] Univ Penn, Inst Med & Engn, Philadelphia, PA 19104 USA

[2] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA USA

[3] Univ Penn, Inst Biomed Informat, Philadelphia, PA 19104 USA

[4] Univ Penn, Dept, Philadelphia, PA 19104 USA

[5] Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA

[6] Univ Penn, Dept Surg, Philadelphia, PA 19104 USA

[7] Univ Penn, Dept Genet, Perelman Sch Med, Philadelphia, PA 19104 USA

[8] Northwestern Univ, Dept Radiol, Chicago, IL 60611 USA

[9] Northwestern Univ, Dept Biomed Engn, Chicago, IL 60611 USA

关键词: Endocardial endothelium;    4D Flow MRI;    Heart;    Shear stress;    RNA sequencing;   

DOI  :  10.1016/j.jbiomech.2016.11.018

来源: Elsevier

【 摘 要 】

Despite substantial evidence for the central role of hemodynamic shear stress in the functional integrity of vascular endothelial cells, hemodynamic and molecular regulation of the endocardial endothelium lining the heart chambers remains understudied. We propose that regional differences in intracardiac hemodynamics influence differential endocardial gene expression leading to phenotypic heterogeneity of this cell layer. Measurement of intracardiac hemodynamics was performed using 4-dimensional flow MRI in healthy humans (n=8) and pigs (n=5). Local wall shear stress (WSS) and oscillatory shear indices (OSI) were calculated in three distinct regions of the LV - base, mid-ventricle (midV), and apex. In both the humans and pigs, WSS values were significantly lower in the apex and midV relative to the base. Additionally, both the apex and midV had greater oscillatory shear indices (OSI) than the base. To investigate regional phenotype, endocardial endothelial cells (EEC) were isolated from an additional 8 pigs and RNA sequencing was performed. A false discovery rate of 0.10 identified 1051 differentially expressed genes between the base and apex, and 321 between base and midV. Pathway analyses revealed apical upregulation of genes associated with translation initiation. Furthermore, tissue factor pathway inhibitor (TFPI; mean 50-fold) and prostacyclin synthase (PTGIS; 5-fold), genes prominently associated with antithrombotic protection, were consistently upregulated in LV apex. These spatiotemporal WSS values in defined regions of the left ventricle link local hemodynamics to regional heterogeneity in endocardial gene expression. (C) 2016 Elsevier Ltd. All rights reserved.

【 授权许可】

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