Abstract
Endothelial dysfunction (ED) is a hallmark of atherosclerosis and is influenced by well-defined risk factors, including hypoxia, dyslipidemia, inflammation, and oscillatory flow. However, the individual and combined contributions to the molecular underpinnings of ED remain elusive. We used global gene expression in human coronary artery endothelial cells to identify gene pathways and cellular processes in response to chemical hypoxia, oxidized lipids, IL-1β induced inflammation, oscillatory flow, and these combined stimuli. We found that clustering of the surrogate risk factors differed from the sum of the individual insults that gave rise to emergent phenotypes such as cell proliferation. We validated these observations in samples of human coronary artery atherosclerotic plaques analyzed using single-cell RNA sequencing. Our findings suggest a hierarchical interaction between surrogates of CV risk factors and the advent of emergent phenotypes in response to combined stimulation in endothelial cells that may influence ED.
Highlights
Endothelial dysfunction (ED) is a hallmark of atherosclerosis and is influenced by well-defined risk factors, including hypoxia, dyslipidemia, inflammation, and oscillatory flow
We evaluated the roles of chemical hypoxia (CoCl2), oxidized lipids (OxPAPC), inflammation (IL-1β), and oscillatory shear stress (OSS) in global gene expression using laminar shear stress (LSS) as a reference to establish the hierarchy of cellular response to these stimuli and the impact of the combined effect of all stimuli, which is frequently observed in patients with cardiovascular disease (Fig. 1)
We first verified the ability of each stimulus to activate or inhibit downstream associated biomarkers: activation of HIF-1α in response to chemical hypoxia (CoCl2, 150 μM); increased ATF3 and reduced CD36 mRNA expression by OxPAPC (50 μg/ ml); increased VCAM-1 protein expression by interleukin 1β (IL-1β) (10 ng/ml)-induced inflammation and misalignment of the endothelial cells (EC) exposed to OSS (± 5 dyn/cm[2] at 1 Hz)
Summary
Endothelial dysfunction (ED) is a hallmark of atherosclerosis and is influenced by well-defined risk factors, including hypoxia, dyslipidemia, inflammation, and oscillatory flow. In the murine EC atlas, 78 sub- clusters of ECs were identified based on more than 32,000 ECs from tissues, including brain, testis, liver, spleen, small intestine, colon, skeletal muscle, and heart These data indicate that the tissue source, as opposed to the type of vascular bed in the blood vessel network, is a critical component that explains most of the heterogeneity of the EC molecular signature[12]. In this context, a significant limitation of current knowledge is the lack of studies using representative ECs from diverse tissues or associated with a particular phenotype. HUVEC represents about 44% of the 360 datasets available in The Endothelial Cell Database (EndoDB)[13] repository (https://endotheliomics.shinyapps.io/endodb/)[13]
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