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bioRxiv · 10.1101/2020.05.15.097931

JAG1-NOTCH4 MECHANOSENSING DRIVES ATHEROSCLEROSIS

Souilhol, C.·Li, X.·Canham, L.·Roddie, H.·Pirri, D.·Tardajos Ayllon, B.·Chambers, E.·Dunning, M.·Ariaans, M.·Li, J.·Fang, Y.·FRAGIADAKI, M.·Ridger, V.·Serbanovic-Canic, J.·De Val, S.·Francis, S.·Chico, T. J.·Evans, P.
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Abstract

Endothelial cell (EC) sensing of fluid shear stress regulates atherosclerosis, a disease of arteries that causes heart attack and stroke. Atherosclerosis preferentially develops at regions of arteries exposed to low oscillatory shear stress (LOSS), whereas high shear regions are protected. We show using inducible EC-specific genetic deletion in hyperlipidaemic mice that the Notch ligands JAG1 and DLL4 have opposing roles in atherosclerosis. While endothelial Jag1 promoted atherosclerosis at sites of LOSS, endothelial Dll4 was atheroprotective. Analysis of porcine and murine arteries and cultured human coronary artery EC exposed to experimental flow revealed that JAG1 and its receptor NOTCH4 are strongly upregulated by LOSS. Functional studies in cultured cells and in mice with EC-specific deletion of Jag1 show that JAG1-NOTCH4 signalling drives vascular dysfunction by repressing endothelial repair. These data demonstrate a fundamental role for JAG1-NOTCH4 in sensing LOSS during disease, and suggest therapeutic targeting of this pathway to treat atherosclerosis.Competing Interest StatementThe authors have declared no competing interest.View Full Text

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Souilhol, C., Li, X., Canham, L., Roddie, H., Pirri, D., Tardajos Ayllon, B., Chambers, E., Dunning, M., Ariaans, M., Li, J., Fang, Y., FRAGIADAKI, M., Ridger, V., Serbanovic-Canic, J., De Val, S., Francis, S., Chico, T. J., Evans, P.. 2020-05-16. JAG1-NOTCH4 MECHANOSENSING DRIVES ATHEROSCLEROSIS. https://doi.org/10.1101/2020.05.15.097931

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