Souilhol, C., Tardajos Ayllon, B., Li, X. et al. (21 more authors) (2022) JAG1-NOTCH4 mechanosensing drives atherosclerosis. Science Advances, 8 (35). eabo7958. ISSN 2375-2548
Abstract
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). https://creativecommons.org/licenses/by/4.0/ |
Keywords: | Animals; Atherosclerosis; Coronary Vessels; Endothelial Cells; Humans; Jagged-1 Protein; Mice; Plaque, Atherosclerotic; Receptor, Notch4; Signal Transduction; Swine |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Sheffield Teaching Hospitals |
Funding Information: | Funder Grant number British Heart Foundation RG/19/10/34506 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 13 Oct 2022 13:37 |
Last Modified: | 13 Oct 2022 13:37 |
Status: | Published |
Publisher: | American Association for the Advancement of Science (AAAS) |
Refereed: | Yes |
Identification Number: | 10.1126/sciadv.abo7958 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:191907 |
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