Abstract--The role of the renin-angiotensin system in oxidative stress-induced apoptosis of endothelial cells (ECs) was investigated using a rat model and cultured ECs. EC apoptosis was induced by 5-minute intra-arterial treatment of a rat carotid artery with 0.01 mmol/L H₂O₂ and was evaluated at 24 hours by chromatin staining of en face specimens with Hoechst 33342. Although activity of angiotensin-converting enzyme in arterial homogenates was not increased, administration of an angiotensin-converting enzyme inhibitor temocapril for 3 days before H₂O₂ treatment inhibited EC apoptosis, followed by reduced neointimal formation 2 weeks later. Also, an angiotensin II type 1 (AT1) receptor blocker (olmesartan) inhibited EC apoptosis, whereas angiotensin II administration accelerated apoptosis independently of blood pressure. Next, cultured ECs derived from a bovine carotid artery were treated with H₂O₂ to induce apoptosis, as evaluated by DNA fragmentation. Combination of angiotensin II and H₂O₂ dose-dependently increased EC apoptosis and 8-isoprostane formation, a marker of oxidative stress. Conversely, temocapril and olmesartan reduced apoptosis and 8-isoprostane formation induced by H₂O₂, suggesting that endogenous angiotensin II interacts with H₂O₂ to elevate oxidative stress levels and EC apoptosis. Neither an AT2 receptor blocker, PD123319, affected H₂O₂-induced apoptosis, nor a NO synthase inhibitor, N^G-nitro-L-arginine methyl ester, influenced the effect of temocapril on apoptosis in cell culture experiments. These results suggest that AT1 receptor signaling augments EC apoptosis in the process of oxidative stress-induced vascular injury.