Endothelial-specific deletion of adipose triglyceride lipase (ATGL) in mice leads to neutral lipid accumulation in blood vessels, endothelial dysfunction, and accelerated atherosclerosis. ATGL is a key enzyme in lipid droplet (LD) metabolism, and its loss in endothelial cells (ECs) causes ER stress and proinflammatory signaling, which impair NO synthesis and endothelial function. This study shows that ATGL deficiency in ECs increases atherosclerotic lesion size in a murine model, highlighting the role of LD dynamics in maintaining endothelial homeostasis and vascular function. The findings suggest that ATGL-mediated LD hydrolysis is essential for preventing endothelial dysfunction and atherosclerosis. The study also demonstrates that ATGL deficiency in ECs upregulates ER stress and inflammatory gene expression, which contributes to atherosclerosis progression. These results provide insights into the mechanisms by which endothelial lipid metabolism influences vascular health and disease.Endothelial-specific deletion of adipose triglyceride lipase (ATGL) in mice leads to neutral lipid accumulation in blood vessels, endothelial dysfunction, and accelerated atherosclerosis. ATGL is a key enzyme in lipid droplet (LD) metabolism, and its loss in endothelial cells (ECs) causes ER stress and proinflammatory signaling, which impair NO synthesis and endothelial function. This study shows that ATGL deficiency in ECs increases atherosclerotic lesion size in a murine model, highlighting the role of LD dynamics in maintaining endothelial homeostasis and vascular function. The findings suggest that ATGL-mediated LD hydrolysis is essential for preventing endothelial dysfunction and atherosclerosis. The study also demonstrates that ATGL deficiency in ECs upregulates ER stress and inflammatory gene expression, which contributes to atherosclerosis progression. These results provide insights into the mechanisms by which endothelial lipid metabolism influences vascular health and disease.