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

Abstract

BACKGROUND AND PURPOSEAs 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 APPROACHMale 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 RESULTSInfusion 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 IMPLICATIONSThis 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. Abbreviations

Effects of Diabetic Hyperglycemia on Central Ang-(1-7)-Mas-R-nNOS Pathways in Spontaneously Hypertensive Rats

“…These effects are not accompanied with changes of arterial BP [23,25], indicating that outcomes of Ang-(1-7) are likely independent of changes in BP. Consistent with the prior findings, in the current report, ICV injection of Ang-(1-7) fails to significantly alter BP in non-diabetic SHR animals; however, it lowers SBP in diabetic SHR animals.…”

“…Prior studies have shown that central chronic administration of Ang-(1-7) increases survival of stroke-prone SHR rats, and improves cerebral blood flow, neurological deficits and brain ischemic tolerance evoked by middle carotid artery occlusion in rats [23,25]. These effects are not accompanied with changes of arterial BP [23,25], indicating that outcomes of Ang-(1-7) are likely independent of changes in BP.…”

“…Thus, in this report, the rats were divided into four groups as: WKY control; WKY with STZ; SHR control and SHR with STZ, respectively. In an additional experiment, Ang-(1-7) (75 µg/kg twice a day) and A779 (150 µg daily) were given via ICV injection [23,25] and tempol (50 mg/kg i.p. daily) was given for 4 weeks.…”

Nitric oxide in cancer metastasis

“…When the production of NO • is obstructed, tumor angiogenesis is suppressed. [57, 58] Cytokine interleukin-33 (IL-33), a regulator of vasculature, was also shown to promote proliferation, migration, angiogenesis and vascular permeability by stimulating endothelial NO • generation through the ST2/TRAF6-Akt-eNOS signaling pathway. [59] In addition, the reduction of NO • formation achieved by knockdown eNOS using siRNA markedly decreased endothelial cells migration in shear stress; however, a supplement of external NO • donor led to a 2-fold recovery in angiogenesis (Fig.…”

Activation of the Neuroprotective Angiotensin-Converting Enzyme 2 in Rat Ischemic Stroke

“…The ACE2/Ang-(1-7)/Mas pathway has been highlighted as a promising target for induction of stroke neuroprotection 4 , and has proven efficacy in reducing infarct size and improving neurological function in preclinical models of ischemic 5-11 and hemorrhagic stroke 12 . Stroke neuroprotection has been demonstrated in both young 5, 6 and aged 10 animals, and methods for activating the axis have included direct intracerebroventricular administration of Ang-(1-7) 5, 7, 11 , delivery of ACE2-primed endothelial progenitor cells 8 , and neuronal ACE2 overexpression 9 . Pharmacological activation of this axis has recently become more feasible with the identification of diminazene aceturate, trade name Berenil®, as an activator of ACE2 13 .…”