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


METHODS
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.


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
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.
Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Nanjing, China.
Teng
T
Jiang
Jin-Tai
JT
Yu
Xi-Chen
XC
Zhu
Qiao-Quan
QQ
Zhang
Meng-Shan
MS
Tan
Lei
L
Cao
Hui-Fu
HF
Wang
Jie
J
Lu
Qing
Q
Gao
Ying-Dong
YD
Zhang
Lan
L
Tan
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000803:Angiotensin I / Q000494:pharmacology*; D000804:Angiotensin II / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D043169:Endostatins / Q000494:pharmacology; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy; D008297:Male; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000502:physiology*; D009952:Ornithine / Q000031:analogs & derivatives / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000502:physiology*
C092006:7-Ala-angiotensin (1-7); D020533:Angiogenesis Inhibitors; D043169:Endostatins; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D000804:Angiotensin II; C065027:N(G)-iminoethylornithine; D000803:Angiotensin I; D009952:Ornithine; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; C118790:angiotensin I (1-7)