Influence of endothelial Cx40 under atheroprone and atheroprotective flow
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ABSTRACT:
PROVIDER: PRJNA486531 | ENA |
REPOSITORIES: ENA
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Project description:Atherosclerosis is a focal disease that preferentially develop in the regions of atheroprone disturbed flow, but less in regions of atheroprotective laminar flow. The mechanisms by which atheroprotective laminar flow prevents atherosclerosis at the epigenetic level remain largely unknown. In this study, we observed that laminar flow decreased histone methyltransferase EZH2, which imposes a repressive epigenetic mark of histone 3 lysine 27 trimethylation (H3K27me3) onto target gene promoters, leading to transcriptional silencing. To evaluate the effect of atheroprotective flow on EZH2 and H3K27me3 dependent genome-wide transcriptional profile, we performed RNA-sequencing study on laminar flow and EZH2 siRNA treated human endothelial cells. Venn diagram was used to compare the common regulated genes by both laminar flow and EZH2 depletion. We found atheroprotective flow and EZH2 depletion altere endothelial gene landscape, which include upregulating atheroprotective genes while downregulating pro-atherosclerotic genes.
2017-09-30 | GSE87534 | GEO
Project description:To profile shear stress-regulated endothelial transcriptomes, we performed RNA-seq with HUVECs subjected to different shear flow conditions, including atheroprotective pulsatile shear (PS, 12±4 dyn/cm2) and atheroprone oscillatory shear (OS, 0.5±4 dyn/cm2), or kept as static control (ST) for four time periods (1, 4, 12 and 24 hours)
2017-05-22 | GSE92506 | GEO
Project description:Objective - When endothelium is cultured in wells swirled on an orbital shaker, cells at the well centre experience putatively proatherogenic flow whereas those near the edge experience putatively atheroprotective flow. Transcellular transport is decreased equally in both regions, consistent with it being reduced by a mediator released from cells in one part of the well and mixed in the swirling medium. Here we identify the mediator and the flow characteristics that stimulate its release. Approach and Results - Medium conditioned by cells swirled at the edge, but not by cells swirled at the centre or cultured under static conditions, significantly reduced transendothelial transport of a low density lipoprotein (LDL)-sized tracer. Mass spectrometry identified follistatin-like 1 (FSTL1) as a candidate mediator. Cells from the swirled edge produced more FSTL1 than cells from the swirled centre or from static wells. Exogenous FSTL1 reduced transendothelial transport of the LDL-sized tracer and of LDL itself. An inhibitor of transcytosis similarly inhibited tracer transport. Exogenous FSTL1 and medium conditioned by cells swirled at the well edge also inhibited TNF-α-induced VCAM-1 and ICAM-1 expression, phosphorylation of IκBα, nuclear translocation of NF-κB, and monocyte adhesion. Conclusions - Putatively atheroprotective flow stimulates production of FSTL1 from cultured endothelial cells. FSTL1 reduces transcellular transport of LDL-sized particles and of LDL itself, and inhibits endothelial activation. If this also occurs in vivo, it may account for the atheroprotective nature of such flow. The identification of a mediator linking flow to LDL transport suggests novel therapeutic strategies.
2021-08-23 | PXD022068 | Pride
Project description:High laminar shear stress (HLSS), as observed in straight parts of arteries, assures a quiescent non-activated endothelium through the induction of the Krüppel-like transcription factors KLF2 and KLF4. Cx40-mediated gap junctional communication contributes to a healthy endothelium by propagating adenosine-evoked anti-inflammatory signals between endothelial cells. As the promoter of the Cx40 gene contains KLF consensus binding sites, we hypothesize that HLSS through the modulation of KLF4, may affect Cx40 expression in ECs, which may affect the quiescent non-activated state of the endothelium.
2019-10-24 | GSE118717 | GEO
Project description:The goal of this study was to find longitudinal transcriptional response of human aortic endothelial cells (HAECs) to pulsatile shear (PS) and oscillatory shear (OS) and compare them with the responses in human umbilical vein endothelial cells (HUVECs) [GSE103672]. PS is associated with an atheroprotective endothelial phenotype, while OS is associated with an atheroprone endothelial phenotype. Using RNASeq method (single-ended 75-bp sequencing on Illumina Hi-seq 4000 instrument), we measured the transcriptional response at 3 time-points (1, 4, and 24 hrs) under PS and OS conditions. Measurements were also taken under static condition (ST, no flow) at t = 0 hr. Three replicates were used for each condition/time-point. Our results indicate that the responses of HAECs and HUVECs are qualitatively similar for endothelial-function relevant genes and several important pathways with a few exceptions, thus demonstrating that HUVECs can be used as a model to investigate the effects of shear on arterial ECs, with some reservations. Our findings show that HAECs exhibit an earlier response or faster kinetics as compared to HUVECs. The comparative analysis in this study offers new insights into the mechanisms of common and disparate stress responses across these two endothelial cell types.
2021-01-13 | GSE160611 | GEO
Project description:This data set reveals the changes of histone modifications and chromatin accessibility in human umbilical vein endothelial cells (HUVECs) under atheroprotective pulsatile shear (PS), atheroprone oscillatory shear (OS), or with KLF4 overexpression. Using ChIP-Seq, we defined the H3K27ac and H3K4me1 enrichment under PS and OS conditions. Using ATAC-seq, we identified the chromatin accessibility under KLF4 overexpression.
2020-03-11 | GSE128390 | GEO
Project description:This data set reveals the changes of histone modifications and chromatin accessibility in human umbilical vein endothelial cells (HUVECs) under atheroprotective pulsatile shear (PS), atheroprone oscillatory shear (OS), or with KLF4 overexpression. Using ChIP-Seq, we defined the H3K27ac and H3K4me1 enrichment under PS and OS conditions. Using ATAC-seq, we identified the chromatin accessibility under KLF4 overexpression.
2020-03-11 | GSE128389 | GEO
Project description:<div><b>OBJECTIVE:</b> Atherosclerotic plaque development is closely associated with the hemodynamic forces applied to endothelial cells (EC). Among these, shear stress (SS) plays a key role in disease development since changes in flow intensity and direction could stimulate an atheroprone or atheroprotective phenotype. EC under low or oscillatory SS (LSS) shows upregulation of inflammatory, adhesion and cellular permeability molecules. On the contrary, cells under high or laminar SS (HSS) increase their expression of protective and anti-inflammatory factors. The mechanism behind SS regulation of an atheroprotective phenotype is not completely elucidated.</div><div><b>APPROACH and RESULTS:</b> Here we used proteomics and metabolomics to better understand the changes in endothelial cells (HUVECs) under in vitro LSS and HSS that promote an atheroprone or atheroprotective profile and how these modifications can be connected to atherosclerosis development. Our data showed that lipid metabolism, in special cholesterol metabolism, was downregulated in cells under LSS. The LDLR showed significant alterations both at the quantitative expression level, as well as regarding post-translational modifications. Under LSS, LDLR was seen at lower concentrations and with a different glycosylation profile. Finally, modulating LDLR with atorvastatin led to the recapitulation of a HSS metabolic phenotype in EC under LSS.</div><div><b>CONCLUSIONS:</b> Altogether, our data suggest that there is significant modulation of lipid metabolism in endothelial cells under different SS intensities and that this could contribute to the atheroprone phenotype of LSS. Statin treatment was able to partially recover the protective profile of these cells.</div>
2019-07-25 | MTBLS739 | MetaboLights
Project description:Doxorubicin suppresses flow-dependent vasoprotective programs triggering a dysfunctional endothelial cell phenotype. Microarrays were used to profile the transcriptome of Doxorubicin treated endothelial cells exposed to atheroprotective flow
2021-02-01 | GSE111129 | GEO
Project description:Blood flow within the vasculature is a critical determinant of endothelial cell (EC) identity and functionality, yet the intricate interplay of various hemodynamic forces and their collective impact on endothelial and vascular responses are not fully understood. Specifically, the role of hydrostatic pressure in the context of flow response is understudied, despite its known significance in vascular development and disease. To address this gap, we developed in vitro models to investigate how pressure influences EC responses to flow. Our study demonstrates that elevated pressure conditions significantly modify shear-induced flow alignment and increase endothelial cell density, a phenomenon often observed in vascular diseases. Utilizing both bulk and single-cell RNA sequencing, we found that while flow is the primary driver of transcriptional changes from static conditions, pressure distinctly modulates this flow response by upregulating gene sets linked to arterial cell phenotypes. Conserved pressure-responsive transcriptional signatures identified in human ECs were upregulated during the onset of circulation in early mouse embryonic vascular development, where pressure was notably associated with transcriptional programs essential to arterial and hemogenic EC fates. Our findings emphasize the necessity of an integrative approach to endothelial cell mechanotransduction, one that encompasses the effects induced by pressure alongside other hemodynamic forces.
2024-03-12 | GSE261063 | GEO