In summary, endothelial P2X7 is essential for atheroprone flow-induced inflammatory signalling in vitro and at atheroprone sites in vivo. Since P2X7 is activated specifically at atheroprone sites linked to dysregulation of localized extracellular ATP levels, we propose its activity contributes to early endothelial dysfunction preceding atherosclerosis development. Here, P2RX7 is linked to atherosclerosis.