Brain ischemia causes systemic Notch1 activity in endothelial cells to drive atherosclerosis

Stroke leads to persistently high risk for recurrent vascular events caused by systemic atheroprogression that is driven by endothelial cell (EC) activation. However, whether and how stroke induces sustained pro-inflammatory and proatherogenic endothelial alterations in systemic vessels remain poorly understood. We showed that brain ischemia induces persistent activation, the upregulation of adhesion molecule VCAM1, and increased senescence in peripheral ECs until 4 weeks after stroke onset. This aberrant EC activity resulted from sustained Notch1 signaling, which was triggered by increased circulating Notch1 ligands DLL1 and Jagged1 after stroke in mice and humans. Consequently, this led to increased myeloid cell adhesion and atheroprogression by generating a senescent, pro-inflammatory endothelium. Notch1- or VCAM1-blocking antibodies and the genetic ablation of endothelial Notch1 reduced atheroprogression after stroke. Our findings revealed a systemic machinery that induces the persistent activation of peripheral ECs after stroke, which paves the way for therapeutic interventions or the prevention of recurrent vascular events following stroke. [Display omitted] •Stroke induces persistent endothelial cell activation and senescence in the periphery•Circulating Notch1 ligands activate peripheral endothelial cells after brain ischemia•Notch1 hyperactivation in endothelium augments myeloid cell adhesion•Post-stroke atheroprogression involves Notch1-induced VCAM1 expression in endothelium Whether stroke induces sustained pro-inflammatory and proatherogenic endothelial alterations in systemic vessels remains poorly understood. Liu et al. find that brain ischemia induces the persistent activation of endothelial Notch1 signaling in the periphery. A sustained increase of circulating Notch1 ligands leads to a senescent, pro-inflammatory endothelium that drives atheroprogression following stroke, which can be therapeutically targeted by blocking antibodies.