DOI: 10.1161/jaha.125.048290 ISSN: 2047-9980

Multiomic Reference Map of Endothelial Mechanosensitive Pathways Under Athero‐ and Erosion‐Prone Flow

Giulio Vidotto, Sara Luzzi, Jonathan D. Humphries, Robert Beal, David G. McVey, Christopher P. Nelson, Thomas R. Webb, Martin J. Humphries, Graham R. Smith, Stephen J. White
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Background

Atherosclerosis develops at arterial sites exposed to disturbed flow, whereas plaque rupture and plaque erosion predominantly occur in regions subjected to elevated flow. The impact of elevated flow on regulation of endothelial gene expression is less well studied; therefore, we undertook a comprehensive analysis of primary human coronary artery endothelial cell gene expression under elevated flow, comparing it to gene expression induced by normal physiological and oscillatory flow.

Methods

Analysis of human coronary artery endothelial cell messenger RNA, microRNA and protein expression cultured under oscillatory shear stress, physiological laminar shear stress, and elevated shear stress (ESS) for 72 hours. Identification of changes in RNA isoform expression and proximity of flow‐responsive genes to established coronary artery disease risk loci were also performed.

Results

A total of 2175 shear‐regulated genes were identified, with 665 uniquely responsive to ESS. Both ESS and oscillatory shear stress induced significant changes in RNA isoform selection, predicted to affect 848 and 580 genes respectively. Signaling pathways regulating coronary artery disease pathogenesis including Hippo, TGFβ/BMP (transforming growth factor beta/bone morphogenetic protein), and IRF (interferon regulatory factor), showed altered RNA isoform selection, which may influence plaque development and plaque erosion. A total of 65% of linkage disequilibrium‐filtered coronary artery disease‐associated genetic variants contained at least 1 oscillatory shear stress or ESS‐regulated gene within 250 kb. Proteomic analysis identified 289 proteins differentially expressed under oscillatory shear stress and 171 under ESS, with notable discordance between messenger RNA and protein changes observed in 28.7% (oscillatory shear stress versus laminar shear stress) and 16.6% (ESS versus laminar shear stress) genes. Additionally, 40 shear‐responsive microRNAs were identified.

Conclusions

Elevated flow elicits a distinct gene expression program in human coronary artery endothelial cells, modulating pathways central to coronary artery disease pathogenesis.

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