Response:
We would like to thank Dr Tsuda for the interest and comments relating to our recent publication.1 We reported that chronic treatment with AT2 receptor (AT2R) agonist CGP42112 prevented brain ischemic injury in conscious spontaneously hypertensive rat. We showed evidence that AT2R stimulation preserved neuronal architecture and motor function, while suggesting that a local vasodilator component would likely contribute to the neuroprotection demonstrated. Indeed, it is well established that AT2R evokes a number of cardiovascular effects that oppose AT1 receptor (AT1R)-mediated actions, including AT2R-mediated vasodilator effects via a nitric oxide (NO)/cGMP-signaling pathway as we have previously reviewed.2,3
As kindly noted by Dr Tsuda, the influence of AT2R stimulation on endothelial NO synthase expression and NO availability, particularly in cerebral vessels and on cerebral blood flow during stroke, is an area of obvious interest. In the context of brain microvasculature, blockade of AT1R results in vasodilatation and subsequently decreases cerebral ischemia by preserving cerebrovascular blood flow.4,5 This vasodilator effect may involve AT2R since candesartan has been shown to increase AT2R expression in brain microvessels6 and AT2R activation evokes cerebral vasodilatation.7 As a point of clarification, renal hypertension8 and aortic banding9 in mice (not exogenous stimulation with an AT2R agonist) led to increased aortic endothelial NO synthase phosphorylation that was associated with upregulated aortic AT2R expression. Nevertheless, an increase in endothelial NO synthase expression and NO bioavailability due to CGP42112 treatment may play a role in the observed neuroprotection in our stroke model, and is part of ongoing investigations in stroke and other studies10 in our laboratory.
However, as we indicated,1 there are likely to be additional mechanisms involved in AT2R-mediated neuroprotection, such as the direct neurotropic effect of AT2R stimulation. Indeed, an AT2R-mediated increase in neuronal survival has been illustrated in cell culture, with Ang II increasing neurite viability and outgrowth in a PD123319-reversible manner. Similarly, a neuroprotective capability of AT2R has been demonstrated in vivo with AT2R being associated with more intense neurite staining after stroke.11 An antioxidant action of AT2R has also been highlighted, with AT2R knockout mice exhibiting elevated levels of superoxide production after stroke,12 a finding that is consistent with the reduction in superoxide production in infarcted tissue that we noted in response to CGP42112.1 Thus, it is likely that there are multiple components to neuroprotection induced during AT2R stimulation, and the potential contribution of endothelial NO synthase and NO availability to this effect should not be ignored.
Acknowledgments
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- Response to Letter by Tsuda
