机构：[1]Department of Infection, Immunity and Cardiovascular Disease, INSIGNEO Institute for In Silico Medicine, and the Bateson Centre, University of Sheffield, Sheffield, UK.[2]Biomolecular Sciences Research Centre, Sheffield Hallam University, Sheffield, UK.[3]School of Pharmacy, Southwest Medical University, LuZhou, Sichuan 646000, P.R. China.[4]Sheffield Bioinformatics Core, Sheffield Institute of Translational Neuroscience, University of Sheffield, Sheffield, UK.[5]Biological Sciences Division, Department of Medicine, University of Chicago, Chicago, IL, USA.[6]Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge, UK.[7]Department of Internal Medicine, Yale Cardiovascular Research Center, New Haven, CT, USA.[8]Department of Bioengineering, Queen Mary University of London, London, UK.[9]Department of Cardiovascular Medicine, Medical Faculty, University of Münster, Münster, Germany.[10]Hirslanden Klinik im Park, Cardiovascular Medicine, Diagnostic and Therapeutic Heart Center AG, 8002 Zürich, Switzerland.[11]BHF Centre of Regenerative Medicine, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.[12]Ludwig Institute for Cancer Research Ltd, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, UK.
Endothelial cell (EC) sensing of disturbed blood flow triggers atherosclerosis, a disease of arteries that causes heart attack and stroke, through poorly defined mechanisms. The Notch pathway plays a central role in blood vessel growth and homeostasis, but its potential role in sensing of disturbed flow has not been previously studied. Here, we show using porcine and murine arteries and cultured human coronary artery EC that disturbed flow activates the JAG1-NOTCH4 signaling pathway. Light-sheet imaging revealed enrichment of JAG1 and NOTCH4 in EC of atherosclerotic plaques, and EC-specific genetic deletion of Jag1 (Jag1ECKO) demonstrated that Jag1 promotes atherosclerosis at sites of disturbed flow. Mechanistically, single-cell RNA sequencing in Jag1ECKO mice demonstrated that Jag1 suppresses subsets of ECs that proliferate and migrate. We conclude that JAG1-NOTCH4 sensing of disturbed flow enhances atherosclerosis susceptibility by regulating EC heterogeneity and that therapeutic targeting of this pathway may treat atherosclerosis.
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出版当年[2022]版：
大类|1 区综合性期刊
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大类|1 区综合性期刊
小类|1 区综合性期刊
第一作者：
第一作者机构：[1]Department of Infection, Immunity and Cardiovascular Disease, INSIGNEO Institute for In Silico Medicine, and the Bateson Centre, University of Sheffield, Sheffield, UK.[2]Biomolecular Sciences Research Centre, Sheffield Hallam University, Sheffield, UK.
共同第一作者：
通讯作者：
通讯机构：[1]Department of Infection, Immunity and Cardiovascular Disease, INSIGNEO Institute for In Silico Medicine, and the Bateson Centre, University of Sheffield, Sheffield, UK.[2]Biomolecular Sciences Research Centre, Sheffield Hallam University, Sheffield, UK.
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