RT Journal Article
SR Electronic
T1 JAG1-NOTCH4 Mechanosensing Drives Atherosclerosis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.05.15.097931
DO 10.1101/2020.05.15.097931
A1 Celine Souilhol
A1 Xiuying Li
A1 Lindsay Canham
A1 Hannah Roddie
A1 Daniela Pirri
A1 Blanca Tardajos Ayllon
A1 Emily V Chambers
A1 Mark J Dunning
A1 Mark Ariaans
A1 Jin Li
A1 Yun Fang
A1 Maria Fragiadaki
A1 Victoria Ridger
A1 Jovana Serbanovic-Canic
A1 Sarah de Val
A1 Sheila E. Francis
A1 Timothy JA Chico
A1 Paul C Evans
YR 2020
UL http://biorxiv.org/content/early/2020/05/16/2020.05.15.097931.abstract
AB 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.