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FOXO1 integrates endothelial hemodynamic, inflammatory and metabolic pathways in atherosclerosis [LSS]

ABSTRACT: Atherosclerosis occurs preferentially in regions of disturbed or low fluid shear stress (FSS), whereas physiological laminar FSS protects against disease by suppressing endothelial inflammation. Pro- vs anti-inflammatory programs are associated with glycolysis vs mitochondrial metabolism, respectively. Endothelial cells (ECs) sensing FSS from blood flow regulate these responses, but the underlying mechanisms are poorly understood. The transcription factor Forkhead box protein O1 (FOXO1) is known to regulate endothelial metabolism, yet its role in FSS-regulated endothelial inflammation remains largely unclear. We found that Oscillatory FSS and inflammatory cytokines induce, whereas physiological FSS inhibits FOXO1 nuclear translocation. RNA sequencing revealed that FOXO1 depletion in ECs upregulates the protective flow-responsive transcription factors KLF2/4 and reduces oscillatory FSS-induced inflammatory genes. Inhibition of FOXO1 nuclear translocation by physiological FSS is mediated via a KLF2-CDK2 pathway, with the latter phosphorylating FOXO1 at S249. Artery ECs-specific deletion of FOXO1 significantly reduces atherosclerotic plaque formation in hyperlipidemic mice. Inhibition of glycolysis attenuates OSS-induced FOXO1 nuclear translocation, suggesting a role for metabolic regulation. Notably, treatment with lactate promotes FOXO1 nuclear localization and lactylation, which is mediated by a lactyltransferase AARS1 (Alanyl-tRNA synthetase). These findings identify FOXO1 as a key mediator linking atheroprone flow and endothelial inflammation, suggesting potential new therapeutic targets for treating atherosclerotic cardiovascular disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE313932 | GEO | 2026/02/24

REPOSITORIES: GEO

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FOXO1 integrates endothelial hemodynamic, inflammatory and metabolic pathways in atherosclerosis [OSS]

Project description:Atherosclerosis occurs preferentially in regions of disturbed or low fluid shear stress (FSS), whereas physiological laminar FSS protects against disease by suppressing endothelial inflammation. Pro- vs anti-inflammatory programs are associated with glycolysis vs mitochondrial metabolism, respectively. Endothelial cells (ECs) sensing FSS from blood flow regulate these responses, but the underlying mechanisms are poorly understood. The transcription factor Forkhead box protein O1 (FOXO1) is known to regulate endothelial metabolism, yet its role in FSS-regulated endothelial inflammation remains largely unclear. We found that Oscillatory FSS and inflammatory cytokines induce, whereas physiological FSS inhibits FOXO1 nuclear translocation. RNA sequencing revealed that FOXO1 depletion in ECs upregulates the protective flow-responsive transcription factors KLF2/4 and reduces oscillatory FSS-induced inflammatory genes. Inhibition of FOXO1 nuclear translocation by physiological FSS is mediated via a KLF2-CDK2 pathway, with the latter phosphorylating FOXO1 at S249. Artery ECs-specific deletion of FOXO1 significantly reduces atherosclerotic plaque formation in hyperlipidemic mice. Inhibition of glycolysis attenuates OSS-induced FOXO1 nuclear translocation, suggesting a role for metabolic regulation. Notably, treatment with lactate promotes FOXO1 nuclear localization and lactylation, which is mediated by a lactyltransferase AARS1 (Alanyl-tRNA synthetase). These findings identify FOXO1 as a key mediator linking atheroprone flow and endothelial inflammation, suggesting potential new therapeutic targets for treating atherosclerotic cardiovascular disease.

2026-02-24 | GSE313931 | GEO

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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.

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Project description:The homeostasis of vascular endothelium is crucial for cardiovascular health and endothelial cell (EC) aging and dysfunction could negatively impact vascular function. Leveraging time-series transcriptomic data obtained from endothelial cells (ECs) subjected to physiological pulsatile flow versus pathophysiological oscillatory flow, we performed principal component analysis (PCA) to identify key genes contributing to divergent transcriptional states of ECs under distinct flow patterns. Through bioinformatics analysis, we identified that a long non-coding RNA (lncRNA) RAMP2- AS1 encoded on the antisense of RAMP2, a determinant of endothelial homeostasis and vascular integrity, is a novel regulator essential for EC homeostasis and function. Knockdown of RAMP2-AS1 inhibited EC angiogenesis and promoted EC senescence, as a result of extensive changes of EC transcriptome. Our study demonstrates an integrative approach to quantifying EC aging based on transcriptome changes, which also identified a number of novel regulators, including protein-coding genes and many lncRNAs involved EC functional modulation.

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