DLL4 promotes partial endothelial-to-mesenchymal transition at atherosclerosis-prone regions of arteries

Flowing blood regulates vascular development, homeostasis and disease by generating wall shear stress which has major effects on endothelial cell (EC) physiology. Low oscillatory shear stress (LOSS) induces a form of cell plasticity called endothelial-to-mesenchymal transition (EndMT). This process has divergent effects; in embryos LOSS-induced EndMT drives the development of atrioventricular valves, whereas in adult arteries it is associated with inflammation and atherosclerosis. The Notch ligand DLL4 is essential for LOSS-dependent valve development; here we investigated whether DLL4 is required for responses to LOSS in adult arteries. Analysis of cultured human coronary artery EC revealed that DLL4 regulates the transcriptome to induce markers of EndMT and inflammation under LOSS conditions. Consistently, genetic deletion of Dll4 from murine EC reduced SNAIL (EndMT marker) and VCAM-1 (inflammation marker) at a LOSS region of the murine aorta. We hypothesized that endothelial Dll4 is pro-atherogenic but this analysis was confounded because endothelial Dll4 negatively regulated plasma cholesterol levels in hyperlipidemic mice. We conclude that endothelial DLL4 is required for LOSS-induction of EndMT and inflammation regulators at atheroprone regions of arteries, and is also a regulator of plasma cholesterol.