Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA343845 | ENA |
REPOSITORIES: ENA
Similar Datasets
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:Role of Fibulin-V (FibV) in disturbed flow induced arterial stiffening and atherosclerosis
| PRJNA922576 | ENA
Project description:Atherosclerosis preferentially occurs in atheroprone vasculature where human umbilical vein endothelial cells (HUVECs) are exposed to disturbed flow. Disturbed flow is associated with vascular inflammation and focal distribution. Recent studies have revealed the involvement of epigenetic regulation in atherosclerosis progression. N6-methyladenosine (m6A) is the most prevalent internal modification of eukaryotic mRNA, but its function in endothelial atherogenic progression remains unclear. Here, we show that m6A mediates the EGFR signaling pathway during EC activation to regulate the atherosclerotic process. Oscillatory stress (OS) reduced the expression of METTL3, the primary m6A methyltransferase. Through m6A sequencing and functional studies, we determined that m6A mediates the mRNA decay of the vascular pathophysiology gene EGFR which leads to EC dysfunction. m6A modification of the EGFR 3’UTR accelerated its mRNA degradation. Double mutation of the EGFR 3’UTR abolished METTL3-induced luciferase activity. Adenovirus-mediated METTL3 overexpression significantly reduced EGFR activation and endothelial dysfunction in the presence of OS. Furthermore, TSP-1, an EGFR ligand, was specifically expressed in atheroprone regions without being affected by METTL3. Inhibition of the TSP-1/EGFR axis by using shRNA and AG1478 significantly ameliorated atherogenesis. Overall, our study revealed that METTL3 alleviates endothelial atherogenic progression through m6A-dependent stabilization of EGFR mRNA, highlighting the important role of RNA transcriptomics in atherosclerosis regulation.
2025-06-20 | GSE299805 | GEO
Project description:Low and disturbed blood flow drives the progression of arterial diseases including atherosclerosis and aneurysms. The endothelial response to flow and its interactions with recruited platelets and leukocytes determine disease progression. Here, we report widespread changes in alternative splicing of pre-mRNA in the flow-activated murine arterial endothelium in vivo. Alternative splicing was suppressed by depletion of platelets and macrophages recruited to the arterial endothelium under low and disturbed flow. Binding motifs for the Rbfox-family are enriched adjacent to many of the regulated exons. Endothelial deletion of Rbfox2, the only family member expressed in arterial endothelium, suppresses a subset of the changes in transcription and RNA splicing induced by low flow. Our data reveal an alternative splicing program activated by Rbfox2 in the endothelium on recruitment of platelets and macrophages and demonstrate its relevance in transcriptional responses during flow-driven vascular inflammation.
2018-01-08 | GSE101826 | GEO
Project description:The mechanisms of arterial stiffness (independent cardiovascular risk factor) are not well understood. Here, we investigated the role of Fibulin V in arterial stiffness and remodeling in response to disturbed blood flow.
2024-10-01 | GSE222583 | GEO
Project description:Schistosomiasis, a prevalent cause of pulmonary hypertension (PH) globally, triggers type 2 inflammation, with interstitial macrophages (IMs) derived from monocytes playing a crucial role. These IMs produce thrombospondin-1 (TSP-1), activating TGF-β and driving PH pathology. Two distinct IM subpopulations were identified: resident FOLR2+ IMs expressing monocyte recruitment factors, and recruited CCR2+ IMs expressing TSP-1. Upon exposure to Schistosoma, the CCR2+ subpopulation expanded. Flow cytometry and single-cell RNA sequencing confirmed these findings, revealing crosstalk between IM subpopulations. The resident FOLR2+ IMs increased expression of monocyte recruitment ligands, while the recruited CCR2+ IMs expressed elevated TSP-1, activating TGF-β and contributing to PH. This study provides insights into the complex interplay of IM subpopulations in Schistosoma-induced PH, shedding light on potential therapeutic targets for this global health concern.
2024-05-08 | GSE254338 | GEO
Project description:Atherosclerosis, which develops in the inner layer of arteries, is the major cause of myocardial infarction and stroke. Atherosclerotic plaques develop preferentially in arterial regions exposed to disturbed blood flow, such as vessel curvatures, bifurcations and branching points, where endothelial cells develop an inflammatory phenotype. How disturbed flow induces endothelial cell inflammation is incompletely understood. We show here that histone H3.3 phosphorylation at serine 31 (H3.3S31) plays a critical role in disturbed flow-induced endothelial inflammation, as it allows the rapid induction of FOS and FOSB, which are required for disturbed flow-induced inflammatory gene expression. We identified protein kinase N1 (PKN1) as the kinase responsible for disturbed flow-induced H3.3S31 phosphorylation. PKN1 becomes activated by disturbed flow in an integrin a5b1-dependent manner and then translocates to the cell nucleus. We found that PKN1 is also involved in the phosphorylation of the AP-1 transcription factor JUN. Mice with endothelium-specific loss of PKN1 or endothelial expression of S31 phosphorylation-deficient mutants of H.3.3 show reduced endothelial inflammation and disturbed flow-induced vascular remodeling in vitro and in vivo. Our data identify a novel mechanism of H3.3S31 phosphorylation which may serve as a target for preventive and therapeutic anti-atherosclerotic strategies.
2024-11-26 | GSE261753 | GEO
Project description:Atherosclerosis, which develops in the inner layer of arteries, is the major cause of myocardial infarction and stroke. Atherosclerotic plaques develop preferentially in arterial regions exposed to disturbed blood flow, such as vessel curvatures, bifurcations and branching points, where endothelial cells develop an inflammatory phenotype. How disturbed flow induces endothelial cell inflammation is incompletely understood. We show here that histone H3.3 phosphorylation at serine 31 (H3.3S31) plays a critical role in disturbed flow-induced endothelial inflammation, as it allows the rapid induction of FOS and FOSB, which are required for disturbed flow-induced inflammatory gene expression. We identified protein kinase N1 (PKN1) as the kinase responsible for disturbed flow-induced H3.3S31 phosphorylation. PKN1 becomes activated by disturbed flow in an integrin a5b1-dependent manner and then translocates to the cell nucleus. We found that PKN1 is also involved in the phosphorylation of the AP-1 transcription factor JUN. Mice with endothelium-specific loss of PKN1 or endothelial expression of S31 phosphorylation-deficient mutants of H.3.3 show reduced endothelial inflammation and disturbed flow-induced vascular remodeling in vitro and in vivo. Our data identify a novel mechanism of H3.3S31 phosphorylation which may serve as a target for preventive and therapeutic anti-atherosclerotic strategies.
2024-11-26 | GSE261755 | GEO
Project description:Atherosclerosis, which develops in the inner layer of arteries, is the major cause of myocardial infarction and stroke. Atherosclerotic plaques develop preferentially in arterial regions exposed to disturbed blood flow, such as vessel curvatures, bifurcations and branching points, where endothelial cells develop an inflammatory phenotype. How disturbed flow induces endothelial cell inflammation is incompletely understood. We show here that histone H3.3 phosphorylation at serine 31 (H3.3S31) plays a critical role in disturbed flow-induced endothelial inflammation, as it allows the rapid induction of FOS and FOSB, which are required for disturbed flow-induced inflammatory gene expression. We identified protein kinase N1 (PKN1) as the kinase responsible for disturbed flow-induced H3.3S31 phosphorylation. PKN1 becomes activated by disturbed flow in an integrin a5b1-dependent manner and then translocates to the cell nucleus. We found that PKN1 is also involved in the phosphorylation of the AP-1 transcription factor JUN. Mice with endothelium-specific loss of PKN1 or endothelial expression of S31 phosphorylation-deficient mutants of H.3.3 show reduced endothelial inflammation and disturbed flow-induced vascular remodeling in vitro and in vivo. Our data identify a novel mechanism of H3.3S31 phosphorylation which may serve as a target for preventive and therapeutic anti-atherosclerotic strategies.
2024-11-26 | GSE261754 | 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