JAG1-NOTCH4 mechanosensing drives atherosclerosis

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 <i>Jag1</i> (<i>Jag1^ECKO</i>) demonstrated that <i>Jag1</i> promotes atherosclerosis at sites of disturbed flow. Mechanistically, single-cell RNA sequencing in <i>Jag1^ECKO</i> mice demonstrated that <i>Jag1</i> 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.