High Shear Stress Enhances Endothelial Permeability in the presence of a CAD Risk Locus
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ABSTRACT:
PROVIDER: PRJNA705304 | ENA |
REPOSITORIES: ENA
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Project description:Single nucleotide polymorphisms are exceedingly common in non-coding loci, yet their impact on cellular dysfunction–especially under stressed conditions associated with coronary artery disease (CAD)–is still unclear. Here we show that when exposed to external stressors, the presence of polymorphisms in the non-coding 9p21.3 locus increases endothelial monolayer and microvessel dysfunction; endothelial cells (ECs) derived from induced pluripotent stem cells of patients homozygous for this risk haplotype (R/R WT) differentiated similarly to their non-risk (N/N) and isogenic knockout (R/R KO) counterparts; monolayers exhibited greater permeability and ROS signaling when the risk locus was present. Addition of the inflammatory cytokine TNFa further enhanced EC monolayer permeability but independent of risk haplotype. When wall shear stress was applied to ECs in a microfluidic vessel, R/R WT vessels were more permeable at lower shear stresses than R/R KO vessels. Transcriptomes of sheared cells clustered more by risk haplotype than by patient or clone, resulting in significant differential regulation of EC function and junction genes versus static conditions. A subset of previously identified CAD risk genes invert expression patterns in the presence of high shear concomitant with aberrant cell-cell adhesion, vessel permeability, and the risk haplotype, suggesting that shear stress could be a unique regulator of non-coding loci and its impact on CAD.
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