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Identification of atheroprone shear stress responsive regulatory elements in endothelial cells

ABSTRACT: While variations in gene transcription networks in models of atherosclerosis have been reported, the underlying changes in the chromatin landscape induced by pro-atherogenic stimuli remain elusive. In the present study, we report changes in chromatin regulatory elements that mediate transcriptional control upon the application of oscillatory shear stress of ±3 dyn/cm2 in primary cultured human umbilical vein endothelial cells (HUVECs) at 6 h time point of oscillatory shear stress stimulation compared to static condition.

ORGANISM(S): Homo sapiens

PROVIDER: GSE116241 | GEO | 2019/03/04

REPOSITORIES: GEO

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Project description:The objective of this study was to advance the understanding of how in vivo arterial shear forces affect vascular endothelial gene expression. Complicated blood flow patterns at arterial branches create small regions that experience fluctuations in shear stress at frequencies higher than the heart rate. To assess whether such temporal variations in shear stress can affect endothelial gene expression, a series of in vitro microarray experiments was performed. The effects of three sinusoidal waveforms (1, 2, and 3 Hz) and one physiological waveform were compared to the expression profiles under steady flow. At each frequency, three levels of mean shear stress (0, 7.5, and 15 dyn/cm2) were used. Porcine aortic endothelial cells were exposed for 24 hours to each combination, replicated four times. Following shear exposure, phase contrast images of the cells were acquired, and RNA was extracted for microarray analysis against about 10,000 porcine oligonucleotides. Cell alignment with the flow was positively correlated with mean shear (p < 0.001) and independent of frequency. A two-way ANOVA identified 232 genes that were differentially regulated by frequency. The frequency sensitive genes were clustered to identify groups of genes exhibiting similar frequency responses. The largest response was seen at 2 Hz. At this frequency, several inflammatory molecules were upregulated, including VCAM, CTGF, TGF-beta2, c-jun, and IL-8, indicating a potential endothelial atherosusceptibility at this frequency. Mean shear significantly affected the expression of ~3,000 genes. Purely oscillatory flow (zero mean shear) enhanced the expression of several growth factors and adhesion molecules (E-selectin, VCAM, MCP-1, IL-8, c-jun), relative to non-reversing flow (15 dyn/cm2 mean shear). The 2 Hz upregulation of certain atherogenic molecules such as VCAM, c-jun, and IL-8 was enhanced as the mean shear was reduced. Thus, the inflammatory response evoked at certain frequencies appears to be exacerbated by low, oscillatory shear. Keywords: Shear stress response

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Identification of atheroprone shear stress responsive regulatory elements in endothelial cells

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