ACE2-Ang(1-7) axis in vascular function

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;·min;) 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;·d;) 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.