Celine Souilhol, Xiuying Li, Lindsay Canham, Hannah Roddie, Daniela Pirri, Blanca Tardajos Ayllon, Emily Chambers, Mark Dunning, Mark Ariaans, Jin Li, Yun Fang, MARIA FRAGIADAKI, Victoria Ridger, Jovana Serbanovic-Canic, Sarah De Val, Sheila Francis, Timothy James Chico, Paul Evans

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Received Date: 5th May 20

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.

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