Angiotensin‐(1–7) induces cerebral ischaemic tolerance by promoting brain angiogenesis in a Mas/eNOS‐dependent pathway

Background and Purpose As a newer component of the renin–angiotensin system, angiotensin‐(1–7) [Ang‐(1–7) ] has been shown to facilitate angiogenesis and protect against ischaemic damage in peripheral tissues. However, the role of Ang‐(1–7) in brain angiogenesis remains unclear. The aim of this study was to investigate whether Ang‐(1–7) could promote angiogenesis in brain, thus inducing tolerance against focal cerebral ischaemia. Experimental Approach Male Sprague‐Dawley rats were i.c.v. infused with Ang‐(1–7), A‐779 (a Mas receptor antagonist), L‐NIO, a specific endothelial NOS (eNOS) inhibitor, endostatin (an anti‐angiogenic compound) or vehicle, alone or simultaneously, for 1–4 weeks. Capillary density, endothelial cell proliferation and key components of eNOS pathway in the brain were evaluated. Afterwards, rats were subjected to permanent middle cerebral artery occlusion (pMCAO), and regional cerebral blood flow (rCBF), infarct volume and neurological deficits were measured 24 h later. Key Results Infusion of Ang‐(1–7) for 4 weeks significantly increased brain capillary density via promoting endothelial cell proliferation, which was accompanied by eNOS activation and up‐regulation of NO and VEGF in brain. These effects were abolished by A‐779 or L‐NIO. More importantly, Ang‐(1–7) improved rCBF and decreased infarct volume and neurological deficits after pMCAO, which could be reversed by A‐779, L‐NIO or endostatin. Conclusions and Implications This is the first evidence that Ang‐(1–7) promotes brain angiogenesis via a Mas/eNOS‐dependent pathway, which enhances tolerance against subsequent cerebral ischaemia. These findings highlight brain Ang‐(1–7)/Mas signalling as a potential target in stroke prevention.