Angiotensin-converting enzyme 2( ACE2)-angiotensin(1-7) [Ang(1-7)]-Mas constitutes the vasoprotective axis and is demonstrated to antagonize the vascular pathophysiological effects of the classical renin-angiotensin system. We hypothesize that upregulation of ACE2-Ang(1-7) signaling protects endothelial function through reducing oxidative stress,thus resulting in beneficial outcome in diabetes. Ex vivo treatment with Ang(1-7) augmented endothelium-dependent relaxation( EDR) in renal arteries from diabetic patients.Both Ang(1-7) infusion via osmotic pump(500 ng·kg~(-1)·min~(-1)) for 2 weeks and exogenous ACE2 overexpression mediated by adenoviral ACE2 via tail vein injection rescued the impaired EDR and flow-mediated dilatation( FMD) in db / db mice. Diminazene aceturate treatment(15 mg·kg~(-1)·d~(-1)) activated ACE2,increased the circulating Ang(1-7) level,and augmented EDR and FMD in db / db mouse arteries. In addition,activation of the ACE2-Ang(1-7) axis reduced reactive oxygen species( ROS) overproduction determined by dihydroethidium staining,CM-H2 DCFDA fluorescence imaging,and chemiluminescence assay in db / db mouse aortas and also in high-glucose-treated endothelial cells. Pharmacological benefits of ACE2-Ang(1-7) upregulation on endothelial function were confirmed in ACE2 knockout mice both ex vivo and in vitro. We elucidate that the ACE2-Ang(1-7)-Mas axis serves as an important signal pathway in endothelial cell protection in diabetic mice,especially in diabetic human arteries. In summary,endogenous ACE2-Ang(1-7) activation or ACE2 overexpression preserves endothelial function in diabetic mice through increasing nitric oxide bioavailability and inhibiting oxidative stress,suggesting the therapeutic potential of ACE2-Ang(1-7) axis activation against diabetic vasculopathy. Angiotensin-converting enzyme 2 (ACE2) -angiotensin (1-7) [Ang (1-7)] - Mas constitutes the vasoprotective axis and is demonstrated to antagonize the vascular pathophysiological effects of the classical renin-angiotensin system. We hypothesize that upregulation of ACE2-Ang (1-7) augmented endothelium-dependent relaxation (EDR) in renal arteries from diabetic patients (2) Angiotensinogen (1-7) infusion via osmotic pump (500 ng · kg -1 min -1) for 2 weeks and exogenous ACE2 overexpression mediated by adenoviral ACE2 via tail vein injection rescued the impaired EDR and Flow-mediated dilatation (FMD) in db / db mice. Diminazene aceturate treatment (15 mg · kg -1 · d -1) activated ACE2, increased the circulating Ang (1-7) level, and augmented EDR and FMD in db / db mouse arteries. In addition, activation of the ACE2-Ang (1-7) axis reduced reactive oxygen s (ROS) overproduction determined by dihydroethidium staining, CM-H2 DCFDA fluorescence imaging, and chemiluminescence assay in db / db mouse aortas and also in high-glucose-treated endothelial cells. Pharmacological benefits of ACE2-Ang (1-7) upregulation on endothelial function were confirmed in ACE2 knockout mice both ex vivo and in vitro. We elucidate that the ACE2-Ang (1-7) -Mas axis serves as an important signal pathway in endothelial cell protection in diabetic mice, especially in diabetic human arteries. In summary, endogenous ACE2-Ang (1-7) activation or ACE2 overexpression preserves endothelial function in diabetic mice through increasing nitric oxide bioavailability and inhibiting oxidative stress, suggesting that therapeutic potential of ACE2-Ang (1-7) axis activation against diabetic vasculopathy .