Neuroprotection after ischemic stroke by activation of angiotensin receptor type 2

Ischemic stroke, representing nearly 90% of all stroke, is a leading cause of death and disability worldwide [1], and will affect one in six persons older than 45 years of age in their remaining lifetime [2]. In addition, with aging of the population, the social and economical burden of the disease will further increase [1]. The only approved treatment is intravenous tissue plasminogen activator (tPA), but it needs to be administered as soon as possible after the event (<4.5 h), meaning that few patients benefit from tPA because they are often admitted too late into the hospital [3]. In the last 40 years, however, there has been a considerable reduction in the incidence of stroke in the USA [4] and improvement in patient's care notably by implementing stroke care units that permit training the stroke specialists able to make rapid diagnosis and initiate thrombolysis [1]; yet, the neuronal consequences of brain ischemia in stroke survivors can be devastating. The severity of neuronal death is obviously directly related to time and area of ischemia; therefore, the faster the recanalization, the less the neuronal death. It seems simple, but there are significant challenges to achieve fast cerebral microcirculation re-flow. First, the brain is in a closed box and unlike for the coronary arteries, a brain artery bypass surgery is not possible. Second, the structure of cerebral arteries is fragile, with thin walls and no adventitia [5,6]. This not only would represent a challenge for a bypass surgery, but also is certainly even an issue for brain artery angioplasty and stenting as recently demonstrated [7]. A third challenge is the geography of the brain circulation, with complex branching, tortuosity and surface cerebral (pial) arteries branching fast and deep into the brain parenchyma. All these specificities make the cerebral arteries a difficult target for treatment. Neuroprotection is, therefore, an equally important clinical goal [8]. As of today, targeting NMDA (acide N-méthyl-D-aspartique) and glutamate and glycine receptors [9], reactive oxygen species [10] and inflammation [11] has not been successful. Neuroprotection is also challenging because, to make a last comparison, brain cells appear much more susceptible to ischemia than the cardiac myocardium. Hence, the window of therapeutic opportunity after stroke is very short; in addition, it is conceptually difficult to apprehend how a therapy aiming at preventing the neuronal damage could reach the penumbra area (area at risk) without prior cerebral artery recanalization. But, let us accept this for a moment. In this current issue of the Journal of Hypertension, Dr Susan Fagan's team [12] bring interesting data, demonstrating that a single administration of the angiotensin receptor type 2 (AT2R) agonist C21 improves the stroke outcome, respectively, at 7 days and 24 h when the compound is administered at re-flow following 90 min and 3 h of occlusion in the middle cerebral artery of adult rats. All parameters fit together: ischemic area and inflammation were reduced, whereas behavioral outcome was significantly improved after C21 administration. These data are therefore in complete agreement with the recent literature supportive of a neuroprotective effect of C21 in stroke models [13–15]. In the present study, the AT2R-dependent neuroprotection of C21 was further tested in the cultured human cerebral microvascular endothelial cells and posed to be associated with the AT2R activation of proangiogenic brain-derived neurotrophic factor (BDNF) expression. In a similar study by the same group that is now in press [16], equally efficient neuroprotection was obtained using a low-dose candesartan, the angiotensin receptor type 1 (AT1R) antagonist. Therefore, direct activation of AT2R or blockade of AT1R have identical neuroprotective effects in rats, including infarct size, inflammation, microvascular density and behavior. The idea that angiotensin receptor blockers (ARBs) have blood pressure (BP)-independent effects on stroke prevention has been proposed [17], and that activation of unopposed AT2R may account for the benefits, the subject of controversies for some years [18]. As reviewed in a recent meta-analysis, large clinical trials do not support any unique BP-independent effects of ARBs on stroke prevention [19] in agreement with the previous analyses of large clinical trial [20,21], including after adjusting for BP differences within the trials [22]. Therefore, why does the preclinical work of Dr Fagan's team, carefully performed and with clear beneficial postischemic stroke outcome, appear to go against the clinical data so far? Different hypotheses could be proposed. An easy argument would be that rats are no patients, but that would be too easy and would deny years of preclinical data predictive of clinical outcomes. On the other hand, it is indeed generally considered that the blockade of the AT1R in patients is associated with an increased stimulation of AT2R, because of the augmented angiotensin II availability. Even if this hypothesis is plausible, it is not easy to demonstrate clinically. Consequently, the effect of the AT2 receptor stimulation, obtained with the administration of a selective agonist, could be different from what is presumed to derive from the activation of the unopposed AT2R by circulating angiotensin II, during selective AT1R blockade. In this regard, whereas direct activation of AT2R or blockade of AT1R have identical neuroprotective effects in rats [12,16], other studies in the different models indicate that the effect of the direct AT2 receptor activation is not always equivalent to the AT1 receptor blockade (often used at doses reducing BP) [23,24], and that the combination of ARBs and AT2R agonists may have a synergistic effect [25–27]. Whether C21 administration might also have AT2-receptor-independent effects [28], in addition to the AT2 receptor-mediated local and systemic effects, remains to be further clarified. A final hypothesis that obviously can be challenged is that the animals used in the study were young, with no cardiovascular risk factors and thus with optimal endothelial function. The proangiogenic effect of C21 [12] or low-dose candesartan [16], indeed, presupposes the functional cerebrovascular endothelial cells able to respond adequately to both C21/angiotensin II (AT2R-mediated) and BDNF stimuli. On the other hand, we know that the cerebrovascular endothelium is dysfunctional with aging [29], and that this dysfunction is hastened and magnified in the presence of risk factors for cardiovascular disease [30]. Consequently, the work presented in this current issue of the Journal of Hypertension shows that AT2R stimulation could improve stroke outcome, and this is undisputable. But, because the mechanism of action involved in the beneficial outcome relies on a functional endothelium, the concept of stimulating AT2R for neuroprotection would be limited to a small population of younger individuals with a limited burden of cardiovascular risk factors together with successful thrombolysis following ischemic stroke. A clinical study to test this hypothesis is needed considering the more than limited therapeutic tool box accessible to physicians in stroke care units to treat a cardiovascular event responsible for approximately one of every 19 deaths in the United States in 2010 [4] and the second cause of death worldwide [31]. ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.

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