ArticleCirculation research2024
EPAS1 Attenuates Atherosclerosis Initiation at Disturbed Flow Sites Through Endothelial Fatty Acid Uptake.
Article in Circulation research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed.
- Ferroptosis-related gene EPAS1 suppresses breast cancer progression by inhibiting M2 macrophage polarization.Discover oncology · 2026Article
- Lipid droplet-associated proteins: Roles in cardiovascular diseases.Journal of lipid research · 2026Review
- Belzutifan for HIF2A-Related Pheochromocytoma and Paraganglioma: A Retrospective Study of Real-World Data.Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists · 2026Article
- Endothelial Metabolic Reprogramming Links Diabetes to Atherosclerosis.Diabetes, metabolic syndrome and obesity : targets and therapy · 2026Review
- Endothelial EPAS1 as a prognostic and therapeutic target in acute myocardial infarction: integrative bioinformatics, Mendelian randomization and experimental validation.Frontiers in pharmacology · 2026Article
- Hypoxia-inducible factors link inflammation and lipid metabolism in atherosclerotic macrophages.Frontiers in cardiovascular medicine · 2026Review
- Characteristics of the Fatty Acid Composition in Elderly Patients with Occupational Pathology from Organophosphate Exposure.Diagnostics (Basel, Switzerland) · 2025Article
- Endothelial cell metabolism in cardiovascular physiology and disease.Nature reviews. Cardiology · 2025Review
- Low Wall Shear Stress Promotes Atheroma via Arterial Iron Accumulation.Arteriosclerosis, thrombosis, and vascular biology · 2025Article
- Metaboloepigenetics: Role in the Regulation of Flow-Mediated Endothelial (Dys)Function and Atherosclerosis.Cells · 2025Review
- Lactylation-related gene signatures identify glioma molecular subtypes with prognostic, immunological, and therapeutic implications.Frontiers in oncology · 2025Article
- Single-cell profiling identifies heterogeneity of the immune microenvironment in healthy, primary and lymph node metastatic BC.Frontiers in immunology · 2025Article
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30 authors.
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Abstract
backgroundAtherosclerotic plaques form unevenly due to disturbed blood flow, causing localized endothelial cell (EC) dysfunction. Obesity exacerbates this process, but the underlying molecular mechanisms are unclear. The transcription factor EPAS1 (HIF2A) has regulatory roles in endothelium, but its involvement in atherosclerosis remains unexplored. This study investigates the potential interplay between EPAS1, obesity, and atherosclerosis.
methodsResponses to shear stress were analyzed using cultured porcine aortic EC exposed to flow in vitro coupled with metabolic and molecular analyses and by en face immunostaining of murine aortic EC exposed to disturbed flow in vivo. Obesity and dyslipidemia were induced in mice via exposure to a high-fat diet or through Leptin gene deletion. The role of
resultsEn face staining revealed EPAS1 enrichment at sites of disturbed blood flow that are prone to atherosclerosis initiation. Obese mice exhibited substantial reduction in endothelial EPAS1 expression. Sulforaphane, a compound with known atheroprotective effects, restored EPAS1 expression and concurrently reduced plasma triglyceride levels in obese mice. Consistently, triglyceride derivatives (free fatty acids) suppressed EPAS1 in cultured EC by upregulating the negative regulator PHD2. Clinical observations revealed that reduced serum EPAS1 correlated with increased endothelial PHD2 and PHD3 in obese individuals. Functionally, endothelial EPAS1 deletion increased lesion formation in hypercholesterolemic mice, indicating an atheroprotective function. Mechanistic insights revealed that EPAS1 protects arteries by maintaining endothelial proliferation by positively regulating the expression of the fatty acid-handling molecules CD36 (cluster of differentiation 36) and LIPG (endothelial type lipase G) to increase fatty acid beta-oxidation.
conclusionsEndothelial EPAS1 attenuates atherosclerosis at sites of disturbed flow by maintaining EC proliferation via fatty acid uptake and metabolism. This endothelial repair pathway is inhibited in obesity, suggesting a novel triglyceride-PHD2 modulation pathway suppressing EPAS1 expression. These findings have implications for therapeutic strategies addressing vascular dysfunction in obesity.
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