<p>The intraplaque endothelium dysfunction and associated inflammation contribute to the progression of atherosclerosis. We previously show that zinc-finger transcription factor Snail is predominantly expressed in embryonic vascular endothelial cells (ECs), and deletion of Snail in ECs induces severe defects in vascular development and thus causes embryonic lethality. Snail is essentially absent at postnatal stage, and inducible deletion of Snail in ECs has no impact on physiological angiogenesis in postnatally developing or adult mice. In this study we investigated whether Snail was reactivated in vascular ECs during pathologically angiogenic process (e.g. the formation of atherosclerotic plaque) or could play a functional role in atherosclerosis progression. We showed that the expression levels of Snail were significantly elevated in ECs of human and mouse atherosclerotic plaques, and associated with the disease severity. In the accelerated and canonical mouse models of atherosclerosis, tamoxifen-inducible, EC-specific Snail deletion significantly reduced intraplaque endothelial dysfunction, inflammation and lipid uptake accompanied by enhanced plaque stability. By conducting scRNA-sequencing in ECs of ApoE^–/–Snail^iΔEC versus ApoE^–/–Snail^fl/fl arterial vessels, we demonstrated that Snail deletion significantly decreased histone acetylation on <i>Ccl5</i> and <i>Cxcl10</i> promoters, thereby decreased CCL5/CXCL10-driven vascular damage and inflammation. Administration with recombinant CXCL10 protein (2 μg/kg, i.v., once per week for three weeks) efficiently restored atherosclerosis in EC-specific Snail-deleted mice. Finally, we developed an orally bioavailable small-molecule Snail inhibitor LFW273 that displayed potent anti-atherosclerotic effects in mice. These results reveal Snail as a promising therapeutic target in atherosclerotic disease.</p>