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Angiotensin‐(1–7) induces cerebral ischaemic tolerance by promoting brain angiogenesis in a M as/ eNOS ‐dependent pathway
Author(s) -
Jiang Teng,
Yu JinTai,
Zhu XiChen,
Zhang QiaoQuan,
Tan MengShan,
Cao Lei,
Wang HuiFu,
Lu Jie,
Gao Qing,
Zhang YingDong,
Tan Lan
Publication year - 2014
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12770
Subject(s) - enos , angiogenesis , ischemia , medicine , endocrinology , cerebral blood flow , renin–angiotensin system , endothelium , angiotensin ii , chemistry , receptor , nitric oxide , nitric oxide synthase , blood pressure
Background and Purpose As a newer component of the renin–angiotensin system, angiotensin‐(1–7) [ A ng‐(1–7) ] has been shown to facilitate angiogenesis and protect against ischaemic damage in peripheral tissues. However, the role of A ng‐(1–7) in brain angiogenesis remains unclear. The aim of this study was to investigate whether A ng‐(1–7) could promote angiogenesis in brain, thus inducing tolerance against focal cerebral ischaemia. Experimental Approach Male S prague‐ D awley rats were i.c.v. infused with A ng‐(1–7), A ‐779 (a M as 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 A ng‐(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, A ng‐(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 A ng‐(1–7) promotes brain angiogenesis via a M as/ eNOS ‐dependent pathway, which enhances tolerance against subsequent cerebral ischaemia. These findings highlight brain A ng‐(1–7)/ M as signalling as a potential target in stroke prevention.