AIMS: Endothelial dysfunction is considered a surrogate marker for cardiovascular disease. Angiotensin II, the principal hormone of the renin angiotensin system, is known to promote atherogenesis. However, other angiotensin peptide fragments such as angiotensin IV possess biological activity that may in fact counter-regulate the actions of angiotensin II. Therefore, we investigated the role of angiotensin IV on the development of endothelial dysfunction in apolipoprotein E-deficient (ApoE-/-) mice. METHODS AND RESULTS: In contrast to their wild-type control, ApoE-/- mice that were fed a high-fat diet had exacerbated endothelial dysfunction, evidenced by impaired endothelium-dependent vasodilation. Chronic infusion of angiotensin IV (1.44 mg/kg per day) in ApoE-/- mice for 2 weeks resulted in significant improvements in endothelial function. Angiotensin IV treatment markedly decreased superoxide levels (dihydroethidium staining fluorescence and L-012 chemiluminescence) and increased endothelial nitric oxide synthase expression (immunoreactivity and western blotting) in aortic tissue. Co-treatment of angiotensin IV with either AT4 receptor antagonist divalinal-Ang IV or AT2 receptor antagonist PD123319 attenuated these changes, indicating involvement of both the AT4 and the AT2 receptors. CONCLUSION: Chronic angiotensin IV treatment in ApoE-/- mice evoked a marked vasoprotective effect that appeared to be mediated by improved NO bioavailability as a result of AT4 and/or AT2 receptor stimulation.