Bos taurus
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ABSTRACT:
PROVIDER: PRJNA140101 | ENA |
REPOSITORIES: ENA
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Project description:Arterial stiffness is a prevalent, independent cardiovascular risk factor, but the underlying mechanisms are not well understood. Wall shear stress and shear-sensitive genes may promote arterial stiffening through clinically important signaling pathways. Our goal was to identify how disturbed blood flow leads to arterial stiffness using the mouse partial carotid ligation model. Here we used our in vivo partial carotid ligation model to induce d-flow in the LCA while the contralateral RCA continues to experience stable laminar flow using the C57BL/6x129SvEv mice, TSP-1 knockout (KO), and C57Bl/6J mice. We compared these to aged (80 week) mice which had increased arterial stiffness due to aging. Changes in gene expression were identified using microarrays that were performed on the endothelial-enriched RNA isolated from the carotids exposed to stable flow (RCA) and compared to disturbed flow (LCA). Arterial stiffness was determined ex vivo by biaxial mechanical testing and in vivo by ultrasound techniques. Myointimal hyperplasia and immunohistochemistry were performed in sectioned carotid arteries. In vitro testing of signaling pathways utilized oscillatory and laminar wall shear stress. Human arteries were tested ex vivo to validate critical results found in the animal model.
2017-09-01 | GSE87199 | GEO
Project description:Chronic high flow can induce arterial remodeling, and this effect is mediated by endothelial cells (ECs) responding to wall shear stress (WSS). To assess how WSS above physiological normal levels affects ECs, we used DNA microarrays to profile EC gene expression under various flow conditions. Cultured bovine aortic ECs were exposed to no flow (0 Pa), normal WSS (2 Pa) and very high WSS (10 Pa) for 24 hrs. Very high WSS induced a distinct expression profile when compared to both no flow and normal WSS. Gene ontology and biological pathway analysis revealed that high WSS modulated gene expression in ways that promote an anti-coagulant, anti-inflammatory, proliferative and pro-matrix remodeling phenotype. A subset of characteristic genes was validated using quantitative polymerase chain reaction (qPCR): Very high WSS upregulated ADAMTS1, PLAU (uPA), PLAT (tPA) and TIMP3, all of which are involved in extracellular matrix processing, with PLAT and PLAU also contributing to fibrinolysis. Downregulated genes included chemokines CXCL5 and IL-8 and the adhesive glycoprotein THBS1 (TSP1). Expressions of ADAMTS1 and uPA proteins were assessed by immunhistochemistry in rabbit basilar arteries experiencing increased flow after bilaterial carotid artery ligation. Both proteins were significantly increased when WSS was elevated compared to sham control animals. Our results indicate that very high WSS elicits a unique transcriptional profile in ECs that favors particular cell functions and pathways that are important in vessel homeostasis under increased flow. In addition, we identify specific molecular targets that are likely to contribute to adaptive remodeling under elevated flow conditions.
2011-12-01 | GSE29376 | GEO
Project description:MEK5 is activated by shear stress in large vessel endothelial cells (ECs) and contributes to the suppression of pro-inflammatory changes in the arterial wall. We used microarray analyses of total RNA from MEK5/CA-transduced HDMECs compared to LacZ control-transduced HDMECs to identify distinct classes of several regulated genes, including KLF4, eNOS, and ICAM. We conclude that MEK5 activation by shear stress may modulate inflammatory responses in the microvasculature, and these actions are partly mediated by KLF4. Total RNA was isolated from 8 separate paired (derived from same primary isolate) MEK5/CA and LacZ transduced HDMEC lines
2010-12-31 | E-GEOD-25145 | biostudies-arrayexpress
Project description:MEK5 is activated by shear stress in large vessel endothelial cells (ECs) and contributes to the suppression of pro-inflammatory changes in the arterial wall. We used microarray analyses of total RNA from MEK5/CA-transduced HDMECs compared to LacZ control-transduced HDMECs to identify distinct classes of several regulated genes, including KLF4, eNOS, and ICAM. We conclude that MEK5 activation by shear stress may modulate inflammatory responses in the microvasculature, and these actions are partly mediated by KLF4.
2010-12-31 | GSE25145 | GEO
Project description:Chronic biomechanical stress elicits remodeling of the arterial wall and causes detrimental arterial stenosis and stiffening. In this context, molecular determinants controlling proliferation and stress responses of vascular smooth muscle cells (VSMCs) have been insufficiently studied. We identified the transcription factor ‘nuclear factor of activated T-cells 5’ (NFAT5) as crucial regulatory element of mechanical stress responses of VSMCs. The relevance of this observation for biomechanically induced arterial remodeling was investigated in mice upon SMC-specific knockdown of NFAT5. While blood pressure levels, vascular architecture and flow-induced collateral growth were not affected in these mice, both hypertension-mediated arterial thickening and muscularization of pulmonary arteries during pulmonary artery hypertension (PAH) were impaired. In all models, a decrease in VSMC proliferation was observed indicating that NFAT5 controls activation of VSMCs in the remodeling arterial wall. Mechanistically, mechanoactivation of VSMCs promotes nuclear translocation NFTA5c upon its phosphorylation at Y143 and dephosphorylation at S1197. As evidenced by transcriptome studies, loss of NFAT5 in mechanoactivated VSMCs impairs expression of gene products controlling cell cycle and transcription/translation. These findings identify NFAT5 as molecular determinant of VSMC responses to biomechanical stress and arterial thickening.
2018-08-10 | GSE106274 | GEO
Project description:Fluid shear stress (FSS) from blood flow sensed by vascular endothelial cells (ECs) determines vessel behavior but regulatory mechanisms are only partially understood. We used cell State Transition Assessment and Regulation (cSTAR), a powerful new computational method, to elucidate EC transcriptomic states under low shear stress (LSS), physiological shear stress (PSS), high shear stress (HSS), and oscillatory shear stress (OSS) that induce vessel inward remodeling, stabilization, outward remodeling or disease susceptibility, respectively. Combined with publicly available EC transcriptomic responses to drug treatments from the LINCS database, this approach inferred a regulatory network controlling EC states and made several novel predictions. Particularly, inhibiting cell cycle dependent kinase (CDK) 2 was predicted to initiate inward vessel remodeling and promote atherogenesis. In vitro, PSS activated CDK2 and induced late G1 cell cycle arrest. In mice, EC deletion of CDK2 triggered inward artery remodeling, pulmonary and systemic hypertension and accelerated atherosclerosis. These results validate use of cSTAR and identify key determinants of normal and pathological artery remodeling.
2024-09-05 | GSE276195 | GEO
Project description:Positive and Negative Spatial Gradients of High Wall Shear Stress Have Different Effects on Endothelial Gene Expression
| PRJNA158301 | ENA
Project description:In order to simulate the effects of shear stress in regions of the vasculature prone to developing atherosclerosis, we subjected human umbilical vein endothelial cells to reversing shear stress, in order to mimic hemodynamic conditions at the wall of the carotid sinus, a site of complex, reversing blood flow and commonly observed atherosclerosis. We compared the effects of reversing shear stress (time-average 1 dyne/cm2, maximum +11 dynes/cm2, minimum -11 dynes/cm2, 1 Hz), arterial steady shear stress (15 dynes/cm2), and low steady shear stress (1 dyne/cm2) in terms of gene expression, cell proliferation, and monocyte adhesiveness. Microarray analysis revealed most differentially expressed genes were similarly regulated by all three shear stress regimens when compared to static culture. Comparisons of the three shear stress regimens to each other allowed identification of 138 genes regulated by low average shear stress and 22 by fluid reversal. Functional assays indicated that low average shear stress induces increased cell proliferation as compared to high shear stress. Reversing shear stress was the only condition that induced monocyte adhesion. Monocyte adhesion was partially inhibited by incubation of the endothelial cells with ICAM-1 blocking antibody. Increased surface heparin sulfate proteoglycan expression was observed in cells exposed to reversing shear stress. When these cells were treated with heparinase III monocyte adhesion was significantly reduced. Our results suggest that low steady shear stress is the major impetus for differential gene expression and cell proliferation, while reversing flow regulates monocyte adhesion.
2009-11-16 | GSE16706 | GEO
Project description:Bone morphogenetic protein (BMP) signaling and fluid shear stress (FSS), the frictional force exerted on endothelial cells by blood flowing over them, have complementary functions in vascular homeostasis and disease development. Both induce a wide range of target genes, not only independently but also in a synergistic or antagonistic manner. Despite thorough research into genetic regulation downstream of BMP9 and FSS, detailed information on how both regulate chromatin accessibility is still missing. Here, we investigated whether BMP9 and FSS act independently, synergistically, or antagonistically in chromatin remodeling. To this end, we employed Assay for Transposase-Accessible Chromatin followed by sequencing (ATAC-seq) to analyze arterial endothelial cells stimulated with BMP9 and FSS either individually or in combination.
2023-06-01 | GSE227588 | GEO
Project description:Pulmonary arterial hypertension (PAH) is a progressive pulmonary vascular disease that culminates in right heart failure. Vascular pathology in PH is characterized by pulmonary vasoconstriction and progressive vascular remodeling processes that affects all layers of the vascular wall (intima, media and adventitia).
2022-06-09 | GSE194080 | GEO