JAG1-NOTCH4 mechanosensing drives atherosclerosis-Reference-Cited by-同舟云学术

JAG1-NOTCH4 mechanosensing drives atherosclerosis

Published:2022-09-02 Issue:35 Volume:8 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Souilhol Celine¹²^ORCID,Tardajos Ayllon Blanca¹^ORCID,Li Xiuying³,Diagbouga Mannekomba R.¹^ORCID,Zhou Ziqi¹^ORCID,Canham Lindsay¹^ORCID,Roddie Hannah¹,Pirri Daniela¹^ORCID,Chambers Emily V.⁴^ORCID,Dunning Mark J.⁴^ORCID,Ariaans Mark¹^ORCID,Li Jin⁵,Fang Yun⁵^ORCID,Jørgensen Helle F.⁶^ORCID,Simons Michael⁷^ORCID,Krams Rob⁸,Waltenberger Johannes⁹¹⁰,Fragiadaki Maria¹,Ridger Victoria¹,De Val Sarah¹¹¹²^ORCID,Francis Sheila E.¹^ORCID,Chico Timothy JA¹,Serbanovic-Canic Jovana¹^ORCID,Evans Paul C.¹^ORCID

Affiliation:

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.

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 ( Jag1 ECKO ) demonstrated that Jag1 promotes atherosclerosis at sites of disturbed flow. Mechanistically, single-cell RNA sequencing in Jag1 ECKO 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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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