Ziqi Zhou , Suze-Anne Korteland , Blanca Tardajos-Ayllon , Junxi Wu , Emily Chambers , Julia Weninck , Michael Simons , Mark Dunning , Torsten Schenkel , Mannekomba Diagbouga , Jolanda Wentzel , Maria Fragiadaki , Paul C. Evans
{"title":"Shear stress is uncoupled from atheroprotective KLK10 in atherosclerotic plaques","authors":"Ziqi Zhou , Suze-Anne Korteland , Blanca Tardajos-Ayllon , Junxi Wu , Emily Chambers , Julia Weninck , Michael Simons , Mark Dunning , Torsten Schenkel , Mannekomba Diagbouga , Jolanda Wentzel , Maria Fragiadaki , Paul C. Evans","doi":"10.1016/j.atherosclerosis.2024.118622","DOIUrl":null,"url":null,"abstract":"<div><h3>Background and aims</h3><div>Physiological shear stress promotes vascular homeostasis by inducing protective molecules in endothelial cells (EC). However, physiological shear stress has been linked to atherosclerosis progression in some individuals with heightened cardiovascular risk. To address this apparent paradox, we hypothesized that diseased arteries may exhibit reduced responsiveness to the protective effects of physiological shear stress. Consequently, we compared the transcriptome of EC exposed to physiological shear stress in healthy arteries <em>versus</em> atherosclerotic conditions.</div></div><div><h3>Methods</h3><div>Employing 3D light sheet imaging and computational fluid dynamics, we identified NOS3 as a marker of physiological shear stress in both healthy and atherosclerotic murine arteries. Single-cell RNA sequencing was performed on EC from healthy (C57BL/6) mice, mildly diseased (<em>Apoe</em><sup><em>−/−</em></sup> normal diet) mice, and highly diseased (<em>Apoe</em><sup><em>−/−</em></sup> high fat diet) mice. The transcriptomes of <em>Nos3</em><sup>high</sup> cells (exposed to physiological shear stress) were compared among the groups.</div></div><div><h3>Results</h3><div><em>Nos3</em><sup>high</sup> EC were associated with several markers of physiological shear stress in healthy arteries. Clustering of <em>Nos3</em><sup>high</sup> EC revealed 8 different EC subsets that varied in proportion between healthy and diseased arteries. Cluster-specific nested functional enrichment of gene ontology terms revealed that <em>Nos3</em><sup>high</sup> EC in diseased arteries were enriched for inflammatory and apoptotic gene expression. These alterations were accompanied by changes in several mechanoreceptors, including the atheroprotective factor KLK10, which was enriched in <em>Nos3</em><sup>high</sup> EC in healthy arteries but markedly reduced in severely diseased arteries.</div></div><div><h3>Conclusions</h3><div>Physiological shear stress is uncoupled from atheroprotective KLK10 within atherosclerotic plaques. This sheds light on the complex interplay between shear stress, endothelial function, and the progression of atherosclerosis in individuals at risk of cardiovascular complications.</div></div>","PeriodicalId":8623,"journal":{"name":"Atherosclerosis","volume":"398 ","pages":"Article 118622"},"PeriodicalIF":4.9000,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Atherosclerosis","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0021915024011948","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
引用次数: 0
Abstract
Background and aims
Physiological shear stress promotes vascular homeostasis by inducing protective molecules in endothelial cells (EC). However, physiological shear stress has been linked to atherosclerosis progression in some individuals with heightened cardiovascular risk. To address this apparent paradox, we hypothesized that diseased arteries may exhibit reduced responsiveness to the protective effects of physiological shear stress. Consequently, we compared the transcriptome of EC exposed to physiological shear stress in healthy arteries versus atherosclerotic conditions.
Methods
Employing 3D light sheet imaging and computational fluid dynamics, we identified NOS3 as a marker of physiological shear stress in both healthy and atherosclerotic murine arteries. Single-cell RNA sequencing was performed on EC from healthy (C57BL/6) mice, mildly diseased (Apoe−/− normal diet) mice, and highly diseased (Apoe−/− high fat diet) mice. The transcriptomes of Nos3high cells (exposed to physiological shear stress) were compared among the groups.
Results
Nos3high EC were associated with several markers of physiological shear stress in healthy arteries. Clustering of Nos3high EC revealed 8 different EC subsets that varied in proportion between healthy and diseased arteries. Cluster-specific nested functional enrichment of gene ontology terms revealed that Nos3high EC in diseased arteries were enriched for inflammatory and apoptotic gene expression. These alterations were accompanied by changes in several mechanoreceptors, including the atheroprotective factor KLK10, which was enriched in Nos3high EC in healthy arteries but markedly reduced in severely diseased arteries.
Conclusions
Physiological shear stress is uncoupled from atheroprotective KLK10 within atherosclerotic plaques. This sheds light on the complex interplay between shear stress, endothelial function, and the progression of atherosclerosis in individuals at risk of cardiovascular complications.
期刊介绍:
Atherosclerosis has an open access mirror journal Atherosclerosis: X, sharing the same aims and scope, editorial team, submission system and rigorous peer review.
Atherosclerosis brings together, from all sources, papers concerned with investigation on atherosclerosis, its risk factors and clinical manifestations. Atherosclerosis covers basic and translational, clinical and population research approaches to arterial and vascular biology and disease, as well as their risk factors including: disturbances of lipid and lipoprotein metabolism, diabetes and hypertension, thrombosis, and inflammation. The Editors are interested in original or review papers dealing with the pathogenesis, environmental, genetic and epigenetic basis, diagnosis or treatment of atherosclerosis and related diseases as well as their risk factors.