JAG1-NOTCH4 mechanosensing drives atherosclerosis.

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SOUILHOL, Celine, TARDAJOS AYLLON, Blanca, LI, Xiuying, DIAGBOUGA, Mannekomba R, ZHOU, Ziqi, CANHAM, Lindsay, RODDIE, Hannah, PIRRI, Daniela, CHAMBERS, Emily V, DUNNING, Mark J, ARIAANS, Mark, LI, Jin, FANG, Yun, JØRGENSEN, Helle F, SIMONS, Michael, KRAMS, Rob, WALTENBERGER, Johannes, FRAGIADAKI, Maria, RIDGER, Victoria, DE VAL, Sarah, FRANCIS, Sheila E, CHICO, Timothy Ja, SERBANOVIC-CANIC, Jovana and EVANS, Paul C (2022). JAG1-NOTCH4 mechanosensing drives atherosclerosis. Science advances, 8 (35): eabo7958. [Article]

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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.
More Information
Official URL:
https://doi.org/10.1126/sciadv.abo7958
Open Access URL:
https://www.science.org/doi/epdf/10.1126/sciadv.ab...
Open Access Version:
Published version
Uncontrolled Keywords:
Coronary Vessels; Endothelial Cells; Animals; Swine; Humans; Mice; Signal Transduction; Atherosclerosis; Plaque, Atherosclerotic; Jagged-1 Protein; Receptor, Notch4; Animals; Atherosclerosis; Coronary Vessels; Endothelial Cells; Humans; Jagged-1 Protein; Mice; Plaque, Atherosclerotic; Receptor, Notch4; Signal Transduction; Swine
Event Location:
United States

Identifiers

Identification Number:
10.1126/sciadv.abo7958
ORCID for Celine Souilhol: ORCID iD orcid.org/0000-0002-3410-353X
ORCID for Blanca Tardajos Ayllon: ORCID iD orcid.org/0000-0001-6466-8366
ORCID for Mannekomba R Diagbouga: ORCID iD orcid.org/0000-0002-2641-5445
ORCID for Ziqi Zhou: ORCID iD orcid.org/0000-0001-6401-2797
ORCID for Lindsay Canham: ORCID iD orcid.org/0000-0003-3005-8855
ORCID for Daniela Pirri: ORCID iD orcid.org/0000-0002-7051-4176
ORCID for Emily V Chambers: ORCID iD orcid.org/0000-0003-1252-8059
ORCID for Mark J Dunning: ORCID iD orcid.org/0000-0002-8853-9435
ORCID for Mark Ariaans: ORCID iD orcid.org/0000-0002-7392-8278
ORCID for Yun Fang: ORCID iD orcid.org/0000-0003-4597-3095
ORCID for Helle F Jørgensen: ORCID iD orcid.org/0000-0002-7909-2977
ORCID for Michael Simons: ORCID iD orcid.org/0000-0003-0348-7734
ORCID for Sarah De Val: ORCID iD orcid.org/0000-0002-2566-2348
ORCID for Sheila E Francis: ORCID iD orcid.org/0000-0001-6552-0339
ORCID for Timothy Ja Chico: ORCID iD orcid.org/0000-0002-7458-5481
ORCID for Jovana Serbanovic-Canic: ORCID iD orcid.org/0000-0002-8835-1491
ORCID for Paul C Evans: ORCID iD orcid.org/0000-0001-7975-681X

Library

Publisher:
American Association for the Advancement of Science (AAAS)
Item Type:
Article
SWORD Depositor:
Symplectic Elements
Depositing User:
Symplectic Elements
Date record made live:
17 Feb 2026 12:29
Last Modified:
17 Feb 2026 12:45
Date of first compliant deposit:
17 February 2026
Date of first compliant Open Access:
17 February 2026
Version of first compliant deposit:
Version of Record
ISSN:
2375-2548
Volume:
8
URI:
https://shura.shu.ac.uk/id/eprint/36816
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