Mus musculus strain:C57BL6
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ABSTRACT:
PROVIDER: PRJNA646233 | ENA |
REPOSITORIES: ENA
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Project description:Recently, we have shown that disturbed flow caused by partial ligation of mouse carotid artery rapidly induces endothelial dysfunction and atherosclerosis within two weeks. To understand the molecular mechanisms by which disturbed flow induces atherosclerosis, we carried out genome-wide microarray study using endothelial RNAs isolated from the flow-disturbed left and the contralateral right common carotid artery (LCA and RCA) in C57BL/6 mice.
2011-03-10 | GSE20741 | GEO
Project description:Recently, we have shown that disturbed flow caused by partial ligation of mouse carotid artery rapidly induces endothelial dysfunction and atherosclerosis within two weeks. To understand the molecular mechanisms by which disturbed flow induces atherosclerosis, we carried out genome-wide microarray study using endothelial RNAs isolated from the flow-disturbed left and the contralateral right common carotid artery (LCA and RCA) in C57BL/6 mice. Total intimal RNAs were obtained from LCA and RCA at 12hr and at 48hr post-ligation. Intimal RNAs from three LCAs or RCAs were pooled to obtain ~30ng total RNA.
2011-03-10 | E-GEOD-20741 | biostudies-arrayexpress
Project description:Atherosclerosis preferentially develops in susceptible regions of the arterial system that are defined by the regional vascular hemodynamics. Previous work in adult castrate male pigs revealed the coexistence of pro- and anti-atherosclerotic profiles in endothelial cell gene expression in disturbed flow regions of arteries in the absence of risk factors for atherogenesis. This study investigates the impact of gender, high fat/high cholesterol diet and regional hemodynamics on arterial endothelial cell gene expression profiles in sexually mature intact pigs.
2007-12-15 | E-CBIL-41 | biostudies-arrayexpress
Project description:Recently, we showed that disturbed flow caused by a partial ligation ofmouse carotid artery rapidly induces atherosclerosis. Analysis of mechanosenstive microRNA in the mouse carotid endothelium. In this study, we examined the microRNAs that respond differentially to blood flow pattern in the mouse carotid endothelium. We surgically induced disturbed blood flow in the left common carotid cartery (LCA) using partial carotid ligation surgery while the right carotid artery was left undisturbed. The hypothesis tested here is that turbulent or disturbed blood flow across the left carotid artery endothelium will affect endothelial genes and microRNAS. Identifying flow-sensitive microRNAs will provide important information about how endothelium responds to d-flow and regulates endothelial function and progression of atherosclerosis. Deter- mining the functional importance of these novel mechanosensitive microRNAS may provide important insights into understanding vascular biology and atherosclerosis.
2014-01-13 | GSE52243 | GEO
Project description:Exposure of the arterial endothelium to low and disturbed flow is a risk factor for the erosion and rupture of atherosclerotic plaques and aneurysms. Circulating and locally produced proteins are known to contribute to an altered matrix composition at the site of lesions, and to contribute to inflammatory processes within the lesions by altering the sub-endothelial matrix. We have previously shown that immune-cell regulated alternative splicing of Fibronectin (FN) protects against flow-induced hemorrhage. Here, we perform quantitative proteomic analysis of enriched extracellular matrix preparations from murine carotid arteries exposed to low and disturbed flow in vivo and examine serum derived and endothelial cell contributions to the sub-endothelial matrix in vitro. Our results reveal the extent of the dynamic alterations in extracellular matrix composition in the acute response to low and disturbed flow, and show how changes in the splicing of FN, a common response in vascular inflammation and remodeling, affects matrix composition.
2022-02-15 | PXD012474 | Pride
Project description:Recently, we showed that disturbed flow caused by a partial ligation ofmouse carotid artery rapidly induces atherosclerosis. Analysis of mechanosenstive microRNA in the mouse carotid endothelium. In this study, we examined the microRNAs that respond differentially to blood flow pattern in the mouse carotid endothelium. We surgically induced disturbed blood flow in the left common carotid cartery (LCA) using partial carotid ligation surgery while the right carotid artery was left undisturbed. The hypothesis tested here is that turbulent or disturbed blood flow across the left carotid artery endothelium will affect endothelial genes and microRNAS. Identifying flow-sensitive microRNAs will provide important information about how endothelium responds to d-flow and regulates endothelial function and progression of atherosclerosis. Deter- mining the functional importance of these novel mechanosensitive microRNAS may provide important insights into understanding vascular biology and atherosclerosis. We used 6- to 8-week-old male C57Bl/6 mice (The Jackson Laboratory) according to the approved Institutional Animal Care and Use Committee protocol by Emory University. Mice were subjected to partial carotid ligation surgery under anesthesia. Briefly, 3 of 4 caudal branches of LCA (left external carotid, internal carotid, and occipital artery) were ligated with 6-0 silk suture, although the superior thyroid artery was left intact. Development of low and oscillatory blood flow in the Left Carotid Artery of each mouse was determined by ultrasound measurements.
2014-01-13 | E-GEOD-52243 | biostudies-arrayexpress
Project description:Biomechanical cues dynamically control major cellular processes but whether genetic variants actively participate in the mechano-sensing mechanisms remain unexplored. Vascular homeostasis is tightly regulated by hemodynamic forces. Exposure to disturbed blood flow at arterial sites of branching and bifurcation causes constant activation of vascular endothelium contributing to the development of atherosclerosis, the major cause of coronary artery disease (CAD). Conversely, unidirectional flow promotes the anti-inflammatory and anti-permeable endothelial phenotype resistant to atherogenesis. Genome-wide association studies (GWAS) have identified chromosome 1p32.2 as one of the loci most strongly associated with CAD susceptibility; however, the causal mechanism related to this CAD locus remain unknown. PhosphoLipid PhosPhatase 3 (PLPP3) is located at 1p32.2 and encodes a phosphatase that suppresses endothelial inflammation and promotes monolayer integrity by hydrolyzing lysophosphatidic acid. Our previous studies demonstrated that PLPP3 is significantly reduced in vascular endothelium exposed to disturbed flow while unidirectional flow significantly increases endothelial PLPP3 expression in vitro and in vivo. In addition, CAD protective allele at 1p32.2 locus is associated with increased PLPP3 in an endothelium-specific manner, shown by expression quantitative trait locus (eQTL). Using Assay for Transposase-Accessible Chromatin using Sequencing (ATAC-Seq), H3K27ac ChIP-Seq, H3K4me2 ChIP-Seq, and luciferase assays, here we identified a mechano-sensitive endothelial enhancer in PLPP3 intron 5 that is dynamically activated by unidirectional flow. Deletion of this enhancer by CRISPR/Cas9-based genome editing causatively reduces endothelial PLPP3 expression and promotes endothelial activation, and moreover, impairs endothelial PLPP3 induction by unidirectional flow. Chromatin accessibility quantitative trait locus (caQTL) mapping, allelic imbalance assay, and luciferase assays further demonstrated that CAD protective allele at rs17114036 in the PLPP3 intron 5 confers an increased enhancer activity. ChIP-PCR and luciferase assays showed that CAD protective allele C at rs17114036 creates a binding site (CACC) for mechano-sensitive transcription factor KLF2, leading to increased enhancer activity under unidirectional flow. These results elucidate the contributory role of CAD genetic predisposition in critical endothelial mechano-transduction mechanisms and suggest that human genetic variants provide a previously unappreciated layer of regulatory control in cellular mechano-sensing mechanisms.
2018-11-19 | GSE112336 | GEO
Project description:Biomechanical cues dynamically control major cellular processes but whether genetic variants actively participate in the mechano-sensing mechanisms remain unexplored. Vascular homeostasis is tightly regulated by hemodynamic forces. Exposure to disturbed blood flow at arterial sites of branching and bifurcation causes constant activation of vascular endothelium contributing to the development of atherosclerosis, the major cause of coronary artery disease (CAD). Conversely, unidirectional flow promotes the anti-inflammatory and anti-permeable endothelial phenotype resistant to atherogenesis. Genome-wide association studies (GWAS) have identified chromosome 1p32.2 as one of the loci most strongly associated with CAD susceptibility; however, the causal mechanism related to this CAD locus remain unknown. PhosphoLipid PhosPhatase 3 (PLPP3) is located at 1p32.2 and encodes a phosphatase that suppresses endothelial inflammation and promotes monolayer integrity by hydrolyzing lysophosphatidic acid. Our previous studies demonstrated that PLPP3 is significantly reduced in vascular endothelium exposed to disturbed flow while unidirectional flow significantly increases endothelial PLPP3 expression in vitro and in vivo. In addition, CAD protective allele at 1p32.2 locus is associated with increased PLPP3 in an endothelium-specific manner, shown by expression quantitative trait locus (eQTL). Using Assay for Transposase-Accessible Chromatin using Sequencing (ATAC-Seq), H3K27ac ChIP-Seq, H3K4me2 ChIP-Seq, and luciferase assays, here we identified a mechano-sensitive endothelial enhancer in PLPP3 intron 5 that is dynamically activated by unidirectional flow. Deletion of this enhancer by CRISPR/Cas9-based genome editing causatively reduces endothelial PLPP3 expression and promotes endothelial activation, and moreover, impairs endothelial PLPP3 induction by unidirectional flow. Chromatin accessibility quantitative trait locus (caQTL) mapping, allelic imbalance assay, and luciferase assays further demonstrated that CAD protective allele at rs17114036 in the PLPP3 intron 5 confers an increased enhancer activity. ChIP-PCR and luciferase assays showed that CAD protective allele C at rs17114036 creates a binding site (CACC) for mechano-sensitive transcription factor KLF2, leading to increased enhancer activity under unidirectional flow. These results elucidate the contributory role of CAD genetic predisposition in critical endothelial mechano-transduction mechanisms and suggest that human genetic variants provide a previously unappreciated layer of regulatory control in cellular mechano-sensing mechanisms.
2018-11-19 | GSE112328 | GEO
Project description:This study investigates the role of endothelial cell (EC) gene expression in the focal origin of atherosclerosis, particularly in response to local hemodynamics. Differential gene expression was profiled in EC isolated from athero-susceptible and athero-protected regions of the normal pig aorta. Specifically, a region of disturbed flow (DF, the inner aortic arch) was compared to a region of undisturbed flow (UF, descending thoracic aorta). Linearly amplified RNA was used to screen nylon filter arrays of 13,824 human cDNAs.
2006-07-21 | E-CBIL-17 | biostudies-arrayexpress
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