Biological Sciences Division
Published August 31, 2022 | Version v1
Journal article Open

JAG1-NOTCH4 mechanosensing drives atherosclerosis

Creators

  • 1. University of Sheffield
  • 2. Southwest Medical University
  • 3. University of Chicago
  • 4. Addenbrooke's Hospital
  • 5. Yale University
  • 6. Queen Mary University of London
  • 7. University of Münster
  • 8. University of Oxford

Description

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.

Data availability

All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper is available at the Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/) submissions GSE206117 (bulk RNA-seq) and GSE207275 (single-cell RNA-seq).

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sciadv.abo7958.pdf

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Additional details

Identifiers

DOI
10.1126/sciadv.abo7958
Other
oai:uchicago.tind.io:10920

Funding

British Heart Foundation
RG/19/10/34506
British Heart Foundation
FS/1735/32929
Fondation Leducq
18CVD03
National Institute for Health and Care Research
John Fell Oxford University Press
Research Fund

UChicago Information

Division(s)
Biological Sciences Division
Department(s)
Medicine