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Multiomic Reference Map of Endothelial Mechanosensitive Pathways Under Athero- and Erosion-Prone Flow
Giulio Vidotto1, Sara Luzzi2, Jonathan D Humphries3
1Bioinformatics Support Unit, Faculty of Medical Sciences Newcastle University Newcastle upon Tyne United Kingdom.
Journal of the American Heart Association
|June 23, 2026
Summary
Elevated shear stress (ESS) uniquely alters endothelial gene expression, impacting pathways crucial for coronary artery disease (CAD) pathogenesis. This study reveals distinct molecular responses to different blood flow patterns in human coronary artery endothelial cells.
Area of Science:
- Cardiovascular Biology
- Genomics and Proteomics
- Endothelial Cell Biology
Background:
- Atherosclerosis development is linked to arterial blood flow patterns.
- Disturbed flow sites are prone to atherosclerosis, while elevated flow regions experience plaque rupture and erosion.
- The endothelial gene expression response to elevated flow remains less understood.
Purpose of the Study:
- To comprehensively analyze gene expression in human coronary artery endothelial cells under elevated shear stress (ESS).
- To compare ESS-induced gene expression changes with those from normal physiological and oscillatory flow.
- To investigate RNA isoform changes and the proximity of flow-responsive genes to coronary artery disease (CAD) risk loci.
Main Methods:
- Cultured human coronary artery endothelial cells under oscillatory, laminar, and elevated shear stress (ESS) for 72 hours.
- Analyzed messenger RNA, microRNA, and protein expression.
- Identified changes in RNA isoform expression and assessed the proximity of flow-responsive genes to CAD risk loci.
Main Results:
- Identified 2175 shear-regulated genes, with 665 uniquely responsive to ESS.
- ESS and oscillatory shear stress significantly altered RNA isoform selection, affecting hundreds of genes.
- Signaling pathways involved in CAD pathogenesis showed altered RNA isoform selection; 65% of CAD-associated genetic variants had nearby shear-responsive genes.
- Proteomic analysis revealed differential protein expression under ESS and oscillatory shear stress, with notable mRNA-protein discordance.
- Identified 40 shear-responsive microRNAs.
Conclusions:
- Elevated flow induces a distinct gene expression program in human coronary artery endothelial cells.
- This program modulates key pathways involved in coronary artery disease pathogenesis.
- Findings offer insights into the molecular mechanisms underlying flow-related cardiovascular disease.
