Angiotensin-(1-7) induces cerebral ischaemic tolerance by promoting brain angiogenesis in a Mas/eNOS-dependent pathway
Angiotensin-(1-7) induces cerebral ischaemic tolerance by promoting brain angiogenesis in a Mas/eNOS-dependent pathway
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DOI：
10.1111/bph.12770
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发表时间：
2014-09-01
影响因子：
7.3
通讯作者：
Tan, Lan
中科院分区：
文献类型：
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作者：
Jiang, Teng;Yu, Jin-Tai;Tan, Lan
背景与目的血管紧张素-（1-7）[Ang-（1 - 7）]作为一种新的肾素-血管紧张素系统的组成成分，在外周组织中具有促进血管生成和保护缺血性损伤的作用。然而，Ang-（1-7）在脑血管生成中的作用尚不清楚。本研究旨在探讨血管紧张素-（1-7）是否能促进脑血管新生，从而诱导对局灶性脑缺血的耐受。实验方法将雄性Sprague-Dawley大鼠单独或同时i. c. v.输注Ang-（1-7）、A-779（Mas受体拮抗剂）、L-NIO、特异性内皮NOS（eNOS）抑制剂、内皮抑制素（抗血管生成化合物）或载体1-4周。评价脑内毛细血管密度、内皮细胞增殖和eNOS通路的关键组分。然后，制作永久性大脑中动脉闭塞（pMCAO）模型，24 h后测定局部脑血流量（rCBF）、梗死体积和神经功能缺损程度。关键结果Ang-（1-7）4周可通过促进内皮细胞增殖，显著增加脑毛细血管密度，并伴有脑内eNOS激活和NO、VEGF表达上调。这些作用被A-779或L-NIO消除。更重要的是，Ang-（1-7）改善pMCAO后的rCBF，减少梗死体积和神经功能缺损，这可以被A-779、L-NIO或endostatin逆转。结论和意义这是第一个证据表明，Ang-（1-7）通过Mas/eNOS依赖性途径促进脑血管生成，从而增强对随后的脑缺血的耐受性。这些发现突出了脑Ang-（1-7）/Mas信号传导作为中风预防的潜在靶点。
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 24h 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.