As our knowledge expands, it is now clear that the renin–angiotensin (Ang) system (RAS) mediates functions other than regulating blood pressure (BP). The RAS plays a central role in the pathophysiology of different neurovascular unit disorders including stroke and retinopathy. Moreover, the beneficial actions of RAS modulation in brain and retina have been documented in experimental research, but not yet exploited clinically. The RAS is a complex system with distinct yet interconnected components. Understanding the different RAS components and their functions under brain and retinal pathological conditions is crucial to reap their benefits. The aim of the present review is to provide an experimental and clinical update on the role of RAS in the pathophysiology and treatment of stroke and retinopathy. Combining the evidence from both these disorders allows a unique opportunity to move both fields forward.

INTRODUCTION

One of the molecular pathways central to the pathophysiology of different neurovascular diseases is the renin–angiotensin (Ang) system (RAS). There is a strong body of experimental evidence that modulating the RAS is associated with endogenous neurovascular restoration and recovery in disorders of the brain and retina. However, clinical data are still lagging with no RAS modulating drug currently approved for use as a direct treatment for cerebrovascular or retinal disorders so far. The aim of this review is to discuss the different pleiotropic actions of modulating RAS in different neurovascular disorders with a special focus on stroke and retinopathy.

Brain and retina as integral parts of the central nervous system

Both brain and retina share the neurovascular unit structure, including neurons, vessels and glia. This neurovascular coupling allows brain and retinal neurons to elicit haemodynamic changes to match their metabolic needs [14]. Moreover, the brain and inner retina both have a tight blood–tissue barrier that plays a fundamental physiological role in controlling the microenvironment and preserving neuronal function. The blood–retina barrier and blood–brain barrier (BBB) are located in the microvascular endothelium of capillaries and covered by the processes of glia (astrocytes and Müller cells) as well as pericytes [14]. Developmentally, the retina is considered as part of the brain that is displaced to the eye, yet still interconnected with neuronal circuits through the optic nerve [5]. In this regard, the retina provides a window to look at the cerebrovascular changes due to its accessibility. Arterioles from retina and brain share anatomy and physiology as well as pathological changes in response to aging, hypertension and metabolic insults [6,7]. Retinal microvasculature can reflect cerebral microvascular diseases such as stroke and dementia [5,8]. For example, retinal microvascular abnormalities have been shown to independently predict the incidence of stroke especially in hypertensive patients with or without diabetes [6,9]. Similarly, diabetic retinopathy (DR) has been independently associated with increased risk of stroke in both type 1 and type 2 diabetics [10,11]. Thus, the retinal arterioles provide a unique opportunity as a surrogate to visualize and measure the progression of different brain disorders especially stroke [5,12,13].

Stroke and retinopathy have similarities as well as differences in their pathologies and treatment. Although both conditions involve ischaemia and subsequent neovascularization, pathogenesis and management of these diseases differ markedly. First, stroke is an acute condition with rapid pathological progression and thus requires immediate intervention within hours of symptom onset. Retinopathy, on the other hand, is a chronic condition, which requires continuous treatment to halt or delay disease progression. Second, whereas reparative angiogenesis is thought to mediate vascular recovery after ischaemic stroke [14,15], uncontrolled angiogenesis plays a central role in the pathogenesis of ischaemic retinopathy such as DR, retinopathy of prematurity (ROP) and age-related macular degeneration (AMD) [16,17]. Lastly, blood pressure (BP) lowering, which is an important component of RAS modulation with drugs, is deemed beneficial for diabetic microvascular complications including retinopathy [18]. BP control has been shown to reduce the incidence but not progression of DR [19]. Likewise, BP lowering is an integral component of primary and secondary stroke prevention. However, for acute stroke management, current guidelines are to avoid reducing BP acutely unless it is extremely high {>220/120 or 185/110 for patients eligible for tissue plasminogen activator (tPA) treatment; [20]}. It is known however that RAS is activated in the pathologies of both stroke and retinopathy causing oxidative stress, inflammation and vasoconstriction [2123]. In the following sections, we will systematically discuss the role of the individual RAS components and their modulation in stroke and retinopathy, combining both experimental and clinical evidence whenever available. This is followed by briefly discussing the RAS modulation in traumatic brain injury (TBI) and cognitive impairment. We will conclude by discussing the interplay among the RAS components and the reasons behind the translational gap between the experimental evidence on RAS modulation in central nervous system (CNS) disorders and their use in the clinic.

RENIN–ANGIOTENSIN SYSTEM IN THE NEUROVASCULAR UNIT

Ang II is a peptide hormone that is generated from Ang I by Ang-converting enzyme (ACE). Ang I itself results from cleavage of angiotensinogen by the enzyme renin. Although once thought to be inactive, the precursor of renin, prorenin, has also been shown to catalyse this cleavage when bound to its receptor, (pro)renin receptor [2427] (Figure 1). Circulating Ang II does not cross the BBB, but local RAS exists that has been implicated in the pathophysiology of different brain and retinal disorders [22,28,29]. Ang II activates two major types of receptors in the brain, Ang II type 1 (AT1R) and type 2 (AT2R) receptors. AT1R is widely expressed in adults and mediates most Ang II effects including inflammatory and vasoconstrictor actions. AT1R is further sub-classified into two types in the rodent brain, AT1a and AT1b. AT2R, which is highly expressed during development, but less so in adulthood, has opposite effects, promoting vasodilation and mitigating inflammation (Figure 2). In general, whereas stimulation of AT1R by Ang II promotes harmful effects under pathological conditions, Ang II stimulation of AT2R is considered protective [30,31]. Physiologically, AT2R actions are usually masked by the more abundant AT1R. However, the AT2R is up-regulated in pathological conditions and does not desensitize or internalize upon stimulation (unlike AT1R) [32]. ACE inhibitors (ACEI) and AT1R blockers (ARB) have long been in clinical use as first line treatment for management of essential hypertension and associated cardiovascular disorders [33]. In addition to the classical ACE/Ang II/ATR axis, there also exists an alternative axis, ACE2/Ang-(1–7)/Mas. Ang II is cleaved by ACE2 to Ang-(1–7) and Ang-(1–7) binds to its receptor, Mas. Together with the AT2R, the ACE2/Ang-(1–7)/Mas axis constitute the protective arms of the RAS as opposed to the ACE/AngII/AT1R arm [3436]. On the other hand, Ang II can also be cleaved by aminopeptidase A to Ang III which is further cleaved to Ang IV by aminopeptidase N. Ang IV was shown to have a binding site distinct from AT1R and AT2R which was named AT4R. There has been a controversy about the nature of the AT4R [37,38]. The enzyme insulin-regulated aminopeptidase (IRAP) is thought to be identical with the AT4R (Figure 1) [39,40]. However, some critics are sceptical of this notion because of IRAP being an enzyme rather than a receptor, which does not reconcile with the presence of agonists and antagonists of AT4R, and rapid downstream signalling mediated by Ang IV/AT4R [37]. A tyrosine kinase receptor (c-MET) has also been proposed as the AT4R but again this needs further confirmation [41]. Ang IV/AT4R has been linked to cognition and memory in the brain [42]. The most recently discovered components of the RAS are alamandine and its receptor, the Mas-related G-coupled receptor type D (MrgD) [43]. Alamandine is considered to have protective actions similar to Ang-(1–7); however, its role in CNS disorders has not yet been examined.

Schematic diagram representing the RAS components

Figure 1
Schematic diagram representing the RAS components

The 10 amino acid peptide, Ang I, is generated from angiotensinogen (AGN) via the enzyme renin. Renin precursor, prorenin, can also catalyse this conversion when bound to its receptor, (pro)renin receptor [(P)RR]. Prorenin binding to (P)RR can also activate Ang II-independent signalling. ACE converts Ang I into Ang II. Ang II can stimulate both AT1R and AT2R. Ang II mediates most of its physiological actions through the well-characterized AT1R. The classical and most studied axis, AGN/Ang I/Ang II/AT1R, is emphasized with thick arrows. Ang II, can be further cleaved to the heptapeptides; Ang-(1–7) through ACE2 or Ang III through aminopeptidase (AMP) A which is further cleaved to the hexa-peptide, Ang IV, by AMP N. Ang-(1–7) stimulates the Mas receptor whereas Ang IV binds to and inhibits AT4R. RAS components in green coloured shapes have been shown to be beneficial for stroke outcome in pre-clinical studies whereas red coloured ones are detrimental. Pharmacological modulators of RAS components are presented in boxes; the ones written in green have been shown to improve stroke outcome whereas the red ones worsen it. Of these pharmacological modulators, aliskiren, ACEI, ARB, diminazine aceturate (DIZE) and C21 are non-peptides. Aliskiren, ACEI and ARB are already in clinical use as anti-hypertensive drugs, DIZE is an anti-protozoal drug, whereas C21 is still in the translational phase.

Figure 1
Schematic diagram representing the RAS components

The 10 amino acid peptide, Ang I, is generated from angiotensinogen (AGN) via the enzyme renin. Renin precursor, prorenin, can also catalyse this conversion when bound to its receptor, (pro)renin receptor [(P)RR]. Prorenin binding to (P)RR can also activate Ang II-independent signalling. ACE converts Ang I into Ang II. Ang II can stimulate both AT1R and AT2R. Ang II mediates most of its physiological actions through the well-characterized AT1R. The classical and most studied axis, AGN/Ang I/Ang II/AT1R, is emphasized with thick arrows. Ang II, can be further cleaved to the heptapeptides; Ang-(1–7) through ACE2 or Ang III through aminopeptidase (AMP) A which is further cleaved to the hexa-peptide, Ang IV, by AMP N. Ang-(1–7) stimulates the Mas receptor whereas Ang IV binds to and inhibits AT4R. RAS components in green coloured shapes have been shown to be beneficial for stroke outcome in pre-clinical studies whereas red coloured ones are detrimental. Pharmacological modulators of RAS components are presented in boxes; the ones written in green have been shown to improve stroke outcome whereas the red ones worsen it. Of these pharmacological modulators, aliskiren, ACEI, ARB, diminazine aceturate (DIZE) and C21 are non-peptides. Aliskiren, ACEI and ARB are already in clinical use as anti-hypertensive drugs, DIZE is an anti-protozoal drug, whereas C21 is still in the translational phase.

Schematic diagram representing AT1R and AT2R actions in the brain after stroke

Figure 2
Schematic diagram representing AT1R and AT2R actions in the brain after stroke

AT1R is widely expressed in adults and mediates most Ang II effects including inflammatory and vasoconstrictor actions. AT2R, which is less expressed in adults and becomes up-regulated with diseases, has opposite effects, thus promotes vasodilation and mitigates inflammation. AT2R counteracts AT1R effects by: (1) mediating opposite actions, (2) mediating opposite signalling via activating phosphatase whereas AT1R activates kinase, or inhibition through direct binding (heterodimerization), and (3) down-regulation of AT1R expression. The balance can be shifted toward the beneficial AT2R actions by either ARB or AT2R stimulation.

Figure 2
Schematic diagram representing AT1R and AT2R actions in the brain after stroke

AT1R is widely expressed in adults and mediates most Ang II effects including inflammatory and vasoconstrictor actions. AT2R, which is less expressed in adults and becomes up-regulated with diseases, has opposite effects, thus promotes vasodilation and mitigates inflammation. AT2R counteracts AT1R effects by: (1) mediating opposite actions, (2) mediating opposite signalling via activating phosphatase whereas AT1R activates kinase, or inhibition through direct binding (heterodimerization), and (3) down-regulation of AT1R expression. The balance can be shifted toward the beneficial AT2R actions by either ARB or AT2R stimulation.

RENIN–ANGIOTENSIN SYSTEM COMPONENTS IN ISCHAEMIC STROKE AND RETINOPATHY

Angiotensin II

Angiotensin II and stroke

Experimental evidence

Experimental studies have highlighted the central role of Ang II in ischaemic stroke injury. Transgenic mice overexpressing Ang II show a larger infarct size at 24 h after permanent middle cerebral artery (MCA) occlusion (pMCAO), which is associated with lower regional cerebral blood flow (CBF) [44]. Similarly, human renin and angiotensinogen double transgenic mice show reduced CBF, larger infarct volume and exaggerated ischaemic brain damage, which was associated with an AT1R-mediated increase in superoxide anion production [45,46]. Reduction in Ang II levels in these mice by treatment with aliskiren, a selective renin inhibitor, improves 7-day stroke neurological outcome [47]. Likewise, both angiotensinogen and AT1aR knockout (KO) mice show smaller lesion volume at 1 but not 24 h [44,48]. Taken together, higher Ang II levels appear to decrease CBF, increase brain damage and worsen stroke outcome through AT1R activation. While Ang II can also provide neuroprotection through AT2R stimulation [49], this effect is usually masked by the predominant AT1R.

Angiotensin II and retinopathy

Experimental evidence

Similar to stroke, studies confirm the deleterious role of Ang II in the pathogenesis of retinopathy. Ang II contributes to DR through increased generation of reactive oxygen species (ROS), formation of advanced glycation end products (AGE) and pericyte apoptosis [50,51]. Miller et al. [51] have shown that Ang II inhibits glyoxalase-1, an enzyme responsible for regulating the level of the AGE precursor methylglyoxal in the diabetic retina. Other studies have confirmed the role of Ang II in RAGE (receptor for AGE)-mediated cellular apoptosis [5254], collectively leading to retinal vascular injury. In addition, Ang II modulates NADPH oxidase (NOX) leading to oxidative stress and increased vascular endothelial growth factor (VEGF) resulting in pathological angiogenesis and leukostasis [5558]. Pericyte loss is one of the initial signs of DR. Ang II acts through AT1R leading to uncoupling of pericytes from the vasculature [59], subsequent migration [60] and eventually apoptosis [50,52]. This was shown to be mediated through ROS generation, which activates the transcription factor NF-κB leading to increased expression of RAGE, which mediates AGE-induced cytotoxicity to retinal pericytes [52]. The effect of renin inhibition in retinopathy will be discussed in the following section.

Angiotensin converting enzyme

ACE and stroke

Experimental evidence

Chronic pre-treatment with the ACEI, captopril, for 28 days has been shown to successfully reduce infarct area by 25% after pMCAO [61]. In contrast, others have shown infarct reduction and neurological improvement upon 5–10-day pre-treatment with the ARB, candesartan, but not the ACEI, ramipril or enalapril [62,63]. Similar results were achieved when comparing ramipril with the ARB, telmisartan, and the combination of both did not provide additional benefit over telmisartan alone [64]. Another group showed infarct volume reduction with ACEI pre-treatment in normotensive Wistar–Kyoto (WKY) but not spontaneously hypertensive rats (SHRs) despite greater BP reduction [65]. We have previously shown neuroprotection with post-stroke treatment with enalapril. The reduction in the infarct size was more pronounced with a hypotensive dose of 10 mg/kg compared with a sub-hypotensive dose of 5 mg/kg enalapril [66]. However, enalapril treatment was not able to achieve the robust functional improvement we previously saw with candesartan under the same experimental conditions [67]. Collectively, it appears that ACEI as a class are less beneficial than ARB in acute ischaemic stroke. One possible explanation could be the decrease in Ang II levels, resulting in less activation of AT2R in the brain [23]. However, further mechanistic studies are warranted to prove this speculation.

Clinical evidence

In primary stroke prevention, BP lowering in general is associated with lower risk of ischaemic stroke in hypertensive patients [68]. The use of ACEI or ARB has been associated with reduced ischaemic stroke risk [6971]. However, a meta-analysis comparing different anti-hypertensive drug classes showed a trend towards lower stroke incidence with diuretics or calcium channel blocker (CCB)-based regimens compared with ACEI [68]. In secondary stroke prevention, the large randomized multicentre trial, PROGRESS (The perindopril protection against recurrent stroke study) showed a reduction in recurrent stroke incidence in patients with a history of ischaemic stroke or transient ischaemic attack (TIA) with the use of ACEI treatment combined with a thiazide diuretic. However, this protection was not achieved with the use of ACEI alone [72]. It is likely that the degree of BP reduction is more important than the use of a specific drug class in secondary stroke prevention [73].

ACE and retinopathy

ACEI have been shown to inhibit pathological angiogenesis in DR both experimentally and clinically.

Experimental evidence

An early study showed that treatment with the ACEI, perindopril, reduced the increased mRNA expression of VEGF and VEGFR-2 and vascular permeability in the retinas of diabetic Sprague–Dawley (SD), rats [74]. Later, a long-term study (36 weeks) that involved treatment of diabetic transgenic Ren-2 rats (which overexpress extra-renal prorenin and renin) with lisinopril (10 mg/kg/day) showed reduction in endothelial cell proliferation and expression of VEGF and its receptor VEGFR-2 [16]. Strong experimental evidence supports the protective effect of renin inhibition in retinopathy. Aliskiren treatment inhibits retinal ischaemia reperfusion injury [75]. Moreover, aliskiren has been shown to be protective against diabetic and oxygen-induced retinal inflammation and vasculopathy in hypertensive transgenic Ren-2 rats [76]. Interestingly, aliskiren exhibited superior protection as compared with ACEI despite greater BP normalization with the later [76]. Further combination of aliskiren with (pro)renin receptor blockade did not provide additional protection [77]. The reason behind the apparent superiority of renin inhibition over ACEI could be attributed to the compensatory increase in renin production and thus incomplete RAS inhibition with the later [22].

Clinical evidence

A meta-analysis of 21 randomized clinical trials looking into the effects of RAS inhibition and DR have shown that ACEI use was associated with reduced risk of DR progression and higher possibility of disease regression. ARB, on the other hand, were associated with a higher possibility of DR regression, but no effect on progression [78]. The fact that similar outcomes were not achieved with other anti-hypertensive medications together with the protective effect of ACEI in normotensive type 1 diabetic patients [79] suggests that ACEI and ARB benefit DR patients with mechanisms beyond their anti-hypertensive effect [80]. The apparent superiority of ACEI over ARB in retinopathy compared with stroke could be explained by the possible involvement of AT2R in retinal pathological angiogenesis, as outlined below. Future studies are needed to test such assumption. Based on this assumption and experimental studies outlined above, renin inhibition with aliskiren should provide, at least, similar protection to that of ACEI. However, this still needs to be confirmed in clinical trials.

Angiotensin type 1 receptor

AT1R and stroke

Experimental evidence

ARB have long been studied as a potential treatment for acute ischaemic stroke. Unlike the case with ACEI, pre-clinical studies with ARB have unequivocally demonstrated the neurovascular protective, anti-inflammatory and antioxidant effects of this class when given as pre- or post-stroke treatment. Chronic pre-treatment with ARB protects from cerebral ischaemia and enhances recovery after stroke in both normotensive and hypertensive rats [81,82]. Similar neuroprotection and behavioural recovery was achieved following post-stroke treatment with ARB [67,83,84]. In our hands, post-stroke treatment with candesartan, achieved neuroprotection and functional recovery after both permanent and transient MCAO using a single hypotensive dose of 1 mg/kg in normotensive rats [85,86]. Using the same dose in hypertensive rats led to exaggerated BP lowering after stroke and we could see candesartan protective effects only with a hypotensive dose [87]. Interestingly, we and others have shown beneficial stroke outcome with sub-hypotensive doses of ARB and when co-administered with tPA suggesting direct protection independent of the effect on BP [88,89]. This is further supported by in vitro evidence that cell damage after 2 h oxygen glucose deprivation (OGD) was higher in primary neurons isolated from wild-type (WT) mice compared with AT1aR KO mice, as measured by lactate dehydrogenase (LDH) release assay. Moreover, pre-treatment with the ARB, losartan, reduced the damage in WT neurons to that of AT1a KO neurons [44]. The protective effects of ARB pre-treatment against OGD/reperfusion or glutamate excitotoxicity were mediated through AT1R blockade and not indirect AT2R stimulation [90,91]. Because of the huge volume of literature published on AT1R blockade in stroke, readers are referred to more detailed review articles dedicated to this topic [9294].

Clinical evidence

Although chronic ARB administration has been shown to reduce the risk of ischaemic stroke [71], acute post-treatment has not shown consistent protection for stroke patients. In the Acute Candesartan Cilexetil Therapy in Stroke Survivors (ACCESS) trial that was conducted on 342 patients, candesartan reduced the cumulative 12-month mortality and number of vascular events with no effect on BP [95]. This was followed by a larger multicentre trial, the Scandinavian Candesartan Acute Stroke Trial (SCAST), which recruited 2029 patients from nine northern European countries [96]. The trial showed no benefit and possible harm from acute treatment of stroke patients with candesartan. This negative outcome was partially attributed to the associated BP lowering. This shifted the attention in recent years to the protective axes of the RAS to reap the benefits of ARB in ischaemic stroke without the BP lowering effect.

AT1R and retinopathy

Experimental evidence

The AT1R has been implicated in the pathological progression of retinal neural damage caused by DR [97,98]. In the early, non-proliferative stage of DR, activation of AT1R expressed on retinal endothelial cells and pericytes is perceived to contribute to the microvascular abnormalities including microaneurysms, acellular capillary formation and hard exudates [99,100]. Streptozotocin (STZ)-induced type 1 diabetic animals were protected from reduced retinal blood flow upon treatment with candesartan, suggesting a retinal vasodilatory response with AT1R blockade [101].

Studies using animal models of proliferative retinopathy have shown that ARB provide retinoprotection by preventing uncontrolled neovascularization [57,102]. Losartan and valsartan have both been shown to prevent pathological neovascularization in the oxygen-induced ischaemic retinopathy model [102106]. Other ARB including telmisartan and candesartan, have been shown to stimulate physiological revascularization of the retina and reduce pathological angiogenesis in the same mouse model [105107]. Remarkably, in spontaneously hypertensive diabetic rats, candesartan was able to reverse retinal neural functional changes including oscillatory potentials [108]. Lastly, in a rat model of chronic glaucoma, continuous pharmacological treatment for 10 weeks using candesartan resulted in significant neuroprotection against retinal ganglion cell loss [109]. Upon comparing the effects of ARB and β1 receptor blockade on retinal dysfunction in diabetic Ren-2 rats, only the ARB reduced retinal vasculopathy and improved electroretinogram despite similar BP normalization, suggesting that these protective effects are independent of BP reduction [110,111].

Clinical evidence

The DIRECT (DIabetic REtinopathy Candesartan Trial) programme, which is the largest clinical trial in retinopathy, assessed the benefits of candesartan in the development and progression of retinopathy in diabetic patients [106,112,113]. In type 1 diabetic patients with established DR, candesartan administration did not prevent the progression of the disease; however, it significantly reduced the incidence of the disease in patients with no or minimal incidence of retinopathy. These results lend further evidence to pre-clinical findings that early intervention with ARB is critical to the retinoprotective effect. In type 2 diabetic patients, candesartan did not significantly affect the risk of retinopathy progression, but significantly increased its regression. By the end of the trial, the overall severity of retinopathy was reduced in candesartan treated patients as compared with the placebo group [106,113]. Post-hoc analysis of the DIRECT study showed that candesartan treatment significantly lowered the microaneurysm score, which was found effective in predicting progression and regression of DR. This indicates that AT1R blockade could slow DR progression in the early stages [114]. Another clinical trial carried out in type 1 diabetic patients found that the odds of retinopathy progression by two steps or more was reduced by 70% with losartan administration compared with placebo [80]. A recent meta-analysis has shown the superiority of ACEI followed by ARBs among other anti-hypertensives to lower the risk of DR progression as well as increase the prospect of disease regression in normotensive patients [78]. However, in hypertensives, data were limited and RAS inhibition did not result in significant improvement. Current guidelines do not recommend the specific use of RAS inhibitors in retinopathy. Therefore, more clinical trials are needed to investigate the duration and intensity of treatment and patient population that will benefit most (patients with or without hypertension and in their early compared with later stages of disease) [115].

Angiotensin type 2 receptor

AT2R and stroke

Experimental evidence

AT2R has been shown to be expressed in the mouse brain in areas that regulate BP, metabolism and stress responses [116]. Interestingly, AT2R has been shown to be up-regulated in the rat brain after stroke [117,118], and has recently been linked to neuroprotection in experimental stroke (Table 1). AT2R stimulation reduces infarct volume whereas AT2R KO mice demonstrate larger infarcts [119,120]. Interestingly, studies from our laboratory and other groups have shown that ARBs mediate their beneficial effects in stroke through unopposed AT2R (and possibly AT4R) stimulation [119,121124]. Until recently, the peptide, CGP42112, remained the only available AT2R agonist with its use being limited by its poor bioavailability and off-target effects [125]. Development of compound 21 (C21) by Vicore Pharma paved the way for studying the function of AT2R in different disease conditions [126].

Table 1
Studies documenting direct AT2R-mediated neuroprotection in vivo
AuthorStudy designTreatmentResults
Iwai et al. [119pMCAO in AT2R-deficient mice, survival 24 h No treatment AT2R-deficient mice showed larger infarct and neurological deficit with more decrease in CBF 
McCarthy et al. [208ET-1-induced MCAO in conscious SHRs, survival 72 h Pre-treatment with CGP42112 ICV (0.1–10 ng/kg/min) CGP42112 dose-dependently reduced cortical infarct volume post-stroke and improved behavioural outcome 
McCarthy et al. [120ET-1 induced MCAO in conscious SHRs, survival 72 h Multiple post-stroke treatments with CGP42112 ICV (3 μg/kg) CGP42112 reduced total infarct volume by ~80% and improved motor function 
Lee et al. [209Thirty minutes tMCAO in mice, survival 24 h Single post-stroke treatment with CGP42112 i.p. (1 mg/kg) CGP42112 improved functional outcomes and reduced infarct volume 
Joseph et al. [130ET-1 induced MCAO in rats, survival 72 h Multiple pre- and post-stroke treatments with C21 ICV and i.p. (0.03 mg/kg/day) Central and systemic treatments reduced infarct size and neurological deficits with no change in CBF 
Min et al. [131pMCAO–AT2R deficient mice, survival 5 days Multiple treatment with C21 i.p. (0.01 mg/kg/day) Treatment reduced the ischaemic area, improved neurological deficit and improved the decrease in CBF after MCAO 
McCarthy et al. [132ET-1 induced MCAO in conscious SHRs, survival 72 h Multiple pre- and post-stroke treatments with C21 ICV C21 decreased infarct volume, improved motor deficit and enhanced microglia activation 
Alhusban et al. [118Three hours and 90 min MCAO in rats, survival 24 h and 7 days respectively Single treatment with C21 i.p. (0.03 mg/kg) at reperfusion C21 reduced infarct size and improved behavioural outcome at 24 h and 7 days, together with increasing vascular density in the ischaemic penumbra. 
AuthorStudy designTreatmentResults
Iwai et al. [119pMCAO in AT2R-deficient mice, survival 24 h No treatment AT2R-deficient mice showed larger infarct and neurological deficit with more decrease in CBF 
McCarthy et al. [208ET-1-induced MCAO in conscious SHRs, survival 72 h Pre-treatment with CGP42112 ICV (0.1–10 ng/kg/min) CGP42112 dose-dependently reduced cortical infarct volume post-stroke and improved behavioural outcome 
McCarthy et al. [120ET-1 induced MCAO in conscious SHRs, survival 72 h Multiple post-stroke treatments with CGP42112 ICV (3 μg/kg) CGP42112 reduced total infarct volume by ~80% and improved motor function 
Lee et al. [209Thirty minutes tMCAO in mice, survival 24 h Single post-stroke treatment with CGP42112 i.p. (1 mg/kg) CGP42112 improved functional outcomes and reduced infarct volume 
Joseph et al. [130ET-1 induced MCAO in rats, survival 72 h Multiple pre- and post-stroke treatments with C21 ICV and i.p. (0.03 mg/kg/day) Central and systemic treatments reduced infarct size and neurological deficits with no change in CBF 
Min et al. [131pMCAO–AT2R deficient mice, survival 5 days Multiple treatment with C21 i.p. (0.01 mg/kg/day) Treatment reduced the ischaemic area, improved neurological deficit and improved the decrease in CBF after MCAO 
McCarthy et al. [132ET-1 induced MCAO in conscious SHRs, survival 72 h Multiple pre- and post-stroke treatments with C21 ICV C21 decreased infarct volume, improved motor deficit and enhanced microglia activation 
Alhusban et al. [118Three hours and 90 min MCAO in rats, survival 24 h and 7 days respectively Single treatment with C21 i.p. (0.03 mg/kg) at reperfusion C21 reduced infarct size and improved behavioural outcome at 24 h and 7 days, together with increasing vascular density in the ischaemic penumbra. 

Abbreviations: ET-1, endothelin-1; tMCAO, transient MCAO.

Compound 21 as a potential stroke treatment

C21 is the first orally available non-peptide AT2R agonist [127]. It is highly selective for the AT2R compared with AT1R (4000-fold) with a Ki value of 0.4 nM for the AT2R receptor and a Ki > 10 μM for the AT1R receptor [127,128]. Being non-peptide, hydrophilic and having a molecular mass of 497.6 g/mol, C21 is soluble in water and most solvents. Whereas C21 is orally available (20%–30%) with a half-life of 4 h in rats [127], it is thought to have poor CNS penetration through the intact BBB [129]. It is perceived to be able to adequately reach the brain after BBB disruption but studies are needed to confirm this.

In 2014, four reports independently verified the neuroprotective effect of C21 treatment after stroke [118,130132]. The first report by Joseph et al. [130] tested C21 in endothelin-1-induced MCAO in rats. The authors showed that pre- or post-stroke treatment with central C21 infusion or multiple systemic doses [0.03 or 0.1 mg/kg/day, intraperitoneal (i.p.)] reduced the infarct size, improved behavioural outcome and ameliorated brain inflammation at 24 and 72 h after stroke. Min et al. [131] adopted a permanent MCAO model using electrocoagulation in mice. The authors again showed neuroprotection, behavioural recovery and decreased inflammation with pre- or post-stroke multiple systemic doses (0.01 mg/kg/day, i.p.) for up to 7 days after stroke. The study was unique in showing reduction in BBB disruption and cerebral oedema with C21. McCarthy et al. [132], employed MCAO in conscious SHRs by administering endothelin-1 to the MCA. Pre-stroke central administration of C21 reduced the infarct area and augmented microglial activation. The authors showed that delayed administration of C21 up to 6 h after stroke, though directly administered into the brain, could achieve neuroprotection. In addition, they also showed cerebral vasorelaxation with C21 ex vivo, corroborating the in vivo increase in CBF seen by Min et al. [131]. In our report, we used temporary MCAO for 3 h or 90 min using a suture MCAO model in the rat. Whereas our results confirmed the neuroprotection, reduced inflammation and behavioural recovery with post-stroke systemic C21 treatment (0.03 mg/kg i.p.), we unequivocally showed no change in BP with treatment using continuous BP telemetry. Furthermore, we showed sustained functional and motor improvement for up to 7 days with only one single dose administered after reperfusion. This single dose achieved a sustained angiogenic response and increased vascularity at 7 days in the ischaemic border zone, an effect that was attributed to brain-derived neurotrophic factor (BDNF) up-regulation with C21 treatment [118]. In these four reports, C21 mediated its neuroprotection through AT2R stimulation as confirmed by the use of AT2R KO mice in Min et al. [131] or the AT2R blocker, PD 123319, in the other three.

AT2R and retinopathy

Experimental evidence

Unlike its neuroprotective and pro-angiogenic effect on brain endothelial cells, the role of the AT2R in retinal angiogenesis remains controversial. One report showed that AT2R blockade decreased retinal VEGF expression in diabetic rats [133]. Similarly, another study showed that blocking AT2R reduced pathological angiogenesis in an oxygen-induced retinal vascularization model. This effect was associated with reduction in the expression of VEGF, its receptor, VEGF-R2, and angiopoietin 2 [134]. Using the same model, a more recent study showed no effect on pathological angiogenesis with AT2R blockade. Interestingly, AT2R stimulation inhibited VEGF-mediated angiogenic response in primary bovine retinal endothelial cells. This anti-angiogenic effect was shown to be mediated through inhibiting VEGF-induced RhoA activation [57]. Therefore, the role of AT2R in retinopathy remains inconclusive and more studies are needed to further dissect the role of AT2R in pathological compared with reparative angiogenesis in retinopathy.

ACE2/Ang-(1–7)/Mas axis

ACE2/Ang-(1–7)/Mas axis in stroke

Experimental evidence

Components of the ACE2/Ang-(1–7)/Mas axis are up-regulated acutely after experimental ischaemic stroke [135]. Intracerebroventricular (ICV) infusion of either Ang 1–7 or the ACE2 activator, diminazine aceturate, attenuates cerebral infarct size and stroke-induced neurological impairment via an anti-inflammatory effect [136138]. Similarly, neuronal overexpression of ACE2 protects mice from MCAO-induced brain infarction and neurological deficits with a more pronounced protection in older animals [139,140]. This protection was mediated via increasing CBF, angiogenic factors and Ang 1–7/Ang II ratio in the brain and was independent of BP change.

Recently, Ang-(1–7) has been shown to promote angiogenesis in the brain [141]. ICV infusion of Ang-(1–7) for 4 weeks increased rat brain endothelial proliferation and capillary density. This 4 week pre-treatment enhanced brain ischaemic tolerance leading to reduced cerebral infarct and behavioural deficits after MCAO. Interestingly, the use of the endothelial nitric oxide synthase (eNOS) inhibitor (L-NIO) or the Mas receptor antagonist, A-779, blocked the angiogenic and neuroprotective effects of Ang 1–7. These findings demonstrate that Ang 1–7 promotes angiogenesis and neuroprotection via Mas receptor stimulation and subsequent eNOS activation. As discussed above, the ACE2/Ang-(1–7)/Mas axis provides similar neuroprotection and neurovascular restoration to that of AT1R blockade and AT2R stimulation, and efforts to target this axis with a clinically feasible treatment are also ongoing (reviewed by Regenhardt et al. [142]).

ACE2/Ang-(1–7)/Mas axis in retinopathy

Experimental evidence

Mas receptor has been shown to be expressed on mouse retinal neurons [143]. Similar to stroke, enhancement of the vasoprotective axis, ACE2/Ang-(1–7)/Mas, counteracts the deleterious effects of Ang II in DR [144,145]. The protective effect of ACE2 appears to be a consequence of Ang II conversion into Ang-(1–7) [145,146]. A study using the STZ-induced diabetic rat model demonstrated a 10-fold increase in the retinal mRNA levels of the vaso-deleterious axis (ACE/Ang II/AT1R) and 30% and 50% reduction in ACE2 and MAS mRNA levels respectively [145]. ACE2 activation was also found to exert neuroprotective effects in an experimental model of glaucoma in rats [147]. Thus, activation of ACE2 could be a potential therapeutic strategy to treat DR as well as optic neuropathy.

Ang IV/AT4R axis

Ang IV/AT4R axis in stroke

Experimental evidence

A less defined component of the brain RAS is the Ang IV/AT4R axis. Ang IV has been shown to be cerebroprotective after ischaemic stroke. When infused through the internal carotid artery after embolic stroke in rats, Ang IV achieved a dose-dependent reduction in infarct size, neurological deficit and mortality at 24 h through NO-dependent redistribution of CBF to the ischaemic areas [148]. Ang IV is a potent inhibitor of IRAP. As anticipated, IRAP KO mice show reduced 24 h infarct volume and increased compensatory CBF after transient 2 h MCAO [149].

Ang IV/AT4R axis in retinopathy

So far, there are no pre-clinical studies on the Ang IV/AT4R axis in retinopathy. Studies on the Ang IV/AT4R axis in retinopathy are needed to examine the role of this under-studied axis.

Summary of RAS actions in brain and retina and potential for future studies

RAS components are expressed in both brain and retina. RAS is activated and plays a central role in the pathophysiology of both stroke and retinopathy. In both conditions, Ang II leads to inflammation, oxidative damage, vasoconstriction and cellular apoptosis. These actions are mostly mediated through AT1R stimulation since inhibition of the Ang II/AT1R axis with ARB reverses these effects [22,93]. In stroke, experimental studies have documented superior protection with ARB as compared with ACEI, which suggests a possible protective role of Ang II apart from its deleterious effects through AT1R. This could possibly be mediated through AT2R stimulation, which has been shown to provide neurovascular protective, anti-inflammatory and BBB preservation effects [150]. In retinopathy, however, ACEI are apparently superior to ARB and renin inhibition provides similar protection. Whereas AT2R plays a beneficial role after stroke, its role in retinopathy still needs to be explored. AT2R stimulation provides an angiogenic effect on brain endothelial cells [118]; however, conflicting reports have been published on the role of AT2R in the retina with regard to neovascularization and more studies are warranted to resolve this discrepancy.

Interestingly, ARB seem to have disease- and context-specific actions regarding their effects on VEGF expression and neovascularization. ACEI and ARB reduce retinal VEGF and pathological neovascularization while stimulating physiological revascularization in rodent ROP. After stroke, ARB have been shown to increase VEGF expression and angiogenesis. Taken together, Ang II/AT1R axis blockade enhances reparative angiogenesis while normalizing pathological neovascularization [151].

Stimulating the ACE2/Ang-(1–7)/Mas axis has been shown to provide neuroprotection and reduce vascular leakage, inflammation and oxidative damage in both stroke and retinopathy [145,147,152,153]. Also, this pathway has been shown to stimulate angiogenesis after stroke but its effect on retinal neovascularization still needs to be studied [141].

The Ang IV/AT4R axis is linked to cognition and research is ongoing to exploit this axis for the treatment of cognitive impairment as discussed later in the present review.

RENIN–ANGIOTENSIN SYSTEM MODULATION IN CEREBRAL ANEURYSMS AND INTRACEREBRAL HAEMORRHAGE

A less common yet more fatal type of stroke is intracranial haemorrhage (approximately 15% of strokes). Two important subtypes are hypertensive intracerebral haemorrhage (ICH) and subarachnoid haemorrhage (SAH) due to ruptured cerebral aneurysms (CA).

Experimental evidence

Studies have documented the benefit of RAS modulation in haemorrhagic stroke and CA. Ang II and ACE are up-regulated in the CA walls [154]. However, the AT1R is not up-regulated in cerebral aneurysmal walls and its blockade (using sub-hypotensive doses of ARB) does not inhibit CA formation [155]. Captopril and losartan reduced CA rupture rate without affecting BP, probably through inhibiting local RAS and subsequent inflammation and oxidative stress [156]. AT1R, among other vasoconstrictor receptors, have been shown to be up-regulated on brain vessels after experimental SAH in a time-dependent manner and correlated with reduction in CBF [157]. Acute treatment with telmisartan after ICH was shown to improve neurological deficit and reduce haemorrhage volume, brain oedema, brain inflammation and oxidative stress [158]. Smeda and Daneshtalab [159] showed superiority of daily treatment with losartan over captopril in reducing BBB disruption and brain herniation at 35 days, while restoring and maintaining CBF auto-regulation after spontaneous haemorrhagic stroke in stroke prone SHRs. Interestingly, neither treatment lowered BP in these animals [159]. Two recent reports have independently documented the protective effects of Ang-(1–7) against CA rupture and subsequent SAH and death, without affecting BP or incidence of aneurysm formation [160,161]. However, these reports pointed out the involvement of different receptors (AT2R compared with Mas) in Ang-(1–7) mediated protection. Lastly, Ang IV has been shown to increase CBF when administered acutely after experimental SAH in rats [162].

Clinical evidence

Polymorphism in the ACE gene has been associated with ICH, especially in Asians [163]. Treatment with ACEIs reduces primary and secondary haemorrhagic stroke risk probably because of their anti-hypertensive effect [164]. Unlike ischaemic stroke, acute BP lowering after ICH seems to be beneficial. The intensive blood pressure reduction in acute cerebral hemorrhage (INTERACT) II trial recently published in the New England Journal of Medicine (NEJM) showed that intensive BP reduction to less than 140 mmHg within 1 h then maintained for 7 days, and commenced within 6 h of symptom onset, led to better outcome [165]. This functional recovery was observed early on (within 1 month) and later at 90 days [166]. Optimal recovery from ICH was observed in hypertensive patients who achieved the greatest systolic BP reductions (≥20 mmHg) in the first hour and maintained it for 7 days [167]. Since different BP lowering agents were used based on availability, it appears that the extent of BP reduction is more important than the pharmacological agent used. ARB treatment failed to benefit ICH patients in a sub-analysis of the SCAST trial. According to the study protocol, BP reduction with candesartan commenced within 30 h (mean of 18 h) and achieved only mild reduction acutely (1.8 mmHg at day 1) as it was given in escalating doses [168]. Since this trial only recruited 274 patients with haemorrhagic strokes, larger clinical trials are warranted to test the effect of earlier intervention with RAS inhibitors in this patient population.

RENIN–ANGIOTENSIN SYSTEM MODULATION AFTER TRAUMATIC BRAIN INJURY

Experimental evidence

RAS modulation provides neuroprotection against experimental TBI. The gene expression of angiotensinogen and AT2R is up-regulated as early as a few hours after induction of TBI in mice [169]. Pre-treatment with a hypotensive dose of the ARB, candesartan (1 mg/kg) or post-treatment with a sub-hypotensive dose (0.1 mg/kg) protects the brain against controlled cortical impact in mice. However, post-treatment with the 1 mg/kg dose failed to show benefit possibly because of the detrimental role of BP reduction [169,170]. In a recent report, both candesartan and telmisartan showed neuroprotection against TBI as well as cognitive and functional improvement when administered in low doses up to 6 h after injury [171]. This neuroprotection was mediated through attenuation of post-traumatic brain inflammation and microglia activation via AT1R blockade and peroxisome proliferator-activated receptor γ (PPAR-γ) activation as well. Similarly, pre-treatment with the AT1R antagonist, ZD 7155, improved CBF and attenuated cerebrovascular dysregulation after fluid percussion injury in newborn pigs [172]. On the other hand, ACE inhibition before induction of TBI increases the motor deficit and exacerbates histological damage in rats, presumably, through impairing substance P breakdown. Both captopril and enalapril achieved the same outcome, suggesting a class effect [173]. The deleterious effect of ACEI was not related to BP reduction since there was no difference in BP between treatment and control groups after trauma. The reasons behind these contradictory results between ARB and ACEI are not known and need further studies to be understood.

AT2R activation following TBI promotes neuroprotection and neurogenesis. Continuous infusion of the AT2R agonist CGP42112A for 3 days immediately after TBI induction in rats resulted in functional recovery and cognitive improvement, together with reduced lesion volume and induction of neurogenesis. These effects were mediated through Akt and ERK activation and up-regulation of the neurotrophic factors, nerve growth factor (NGF) and BDNF [174]. AT2R stimulation is also involved in heat acclimation (HA) conferred neuroprotection from TBI. HA increases hypothalamic AT2R expression and treatment with the AT2R antagonist, PD123319, diminishes the HA-mediated motor and cognitive improvement after TBI [175]. Clinically, approximately one-third of TBI patients experience hypotension [176,177] and RAS modulation has not been attempted in clinical trials of TBI.

RENIN–ANGIOTENSIN SYSTEM AND COGNITIVE IMPAIRMENT

Experimental evidence

Activation of RAS results in cognitive dysfunction [178180] and its modulation has been associated with improving cognition both experimentally and clinically. In experimental models, AT1R blockade, AT2R stimulation, renin or ACE inhibition, ACE2 activation and AT4R inhibition have all been shown to improve cognition. Pre-treatment with olmesartan attenuated cognitive impairment in an acute Alzheimer's disease (AD) mouse model induced by ICV injection of β-amyloid 1–40. This effect was achieved through improving cerebrovascular dysfunction and decreasing oxidative stress [178]. In the same mouse model of AD, the brain penetrating ACEI, perindopril, but not the non-brain penetrating ACEI, enalapril and imidapril, could prevent cognitive impairment without affecting brain Aβ deposition [181,182]. Similarly, centrally active ACEI [183] and ARB [184] ameliorate cognitive impairment in vascular dementia models achieved by chronic cerebral hypo-perfusion, as well as other models of cognitive impairment [185187]. Interestingly, the beneficial effect of ACEI and ARB were independent of their BP lowering activity since sub-hypotensive doses of ARB [184] were shown to be beneficial and BP lowering with non-brain penetrating ACEI or other anti-hypertensives did not improve cognitive function under similar experimental conditions. Instead, other pleiotropic effects, including PPAR-γ activation [188,189] and reduced BBB permeability [190], have been suggested to ameliorate cognitive dysfunction.

Modulation of RAS by other interventions has achieved similar results to those of ARB and ACEI. Direct stimulation of AT2R with C21 enhances cognitive function and spatial memory in normal mice and prevents cognitive decline in an AD mouse model with ICV injection of amyloid-β (1–40) [191]. Combination treatment with C21 and memantine, a mainstay treatment of AD, synergistically prevented cognitive decline in type 2 diabetic mice [192]. Interestingly, a very recent study showed opposing effects on vascular cognitive impairment with C21. C21 improved spatial reference memory in mice with chronic cerebral hypo-perfusion but worsened that of shams [193]. Inhibition of renin by aliskiren [194] or administration of Ang-(1–7) [195] ameliorates vascular dementia caused by chronic cerebral hypo-perfusion. Likewise, there is a strong body of literature documenting the memory enhancing effect of Ang IV as reviewed by Albiston et al. [196]. Interestingly, a very recent study showed that losartan prevents cognitive deficits in a human amyloid precursor protein transgenic mouse model of AD through normalizing AT4R expression [197]. Therefore, there have been great efforts in developing Ang IV analogues and AT4R inhibitors that can be used as treatment for AD [38,196], however their clinical efficacy has yet to be determined.

Clinical evidence

Recent reports have confirmed the beneficial role of ACEI in AD patients. A retrospective analysis of data from doxycycline and rifampicin for AD study showed that the use of a centrally acting ACEI was associated with a reduced rate of cognitive decline in patients with mild to moderate AD [198]. This finding was corroborated with another prospective multicentre cohort study [199]. Results from the PROGRESS study show that secondary stroke prevention with perindopril alone or combination with indapamide reduced the risks of dementia and cognitive decline associated with recurrent stroke [200]. Whereas this was attributed to the reduction in recurrent strokes due to BP lowering, ACEI are thought to be beneficial in reducing dementia risk in addition to their BP lowering effect, with a more pronounced effect with the BBB-crossing ACEI, such as captopril and perindopril [201]. The Study on COgnition and Prognosis in the Elderly (SCOPE) trial tested the effect of BP lowering with the ARB, candesartan, on cognitive decline and dementia in the elderly. The study showed a major reduction in non-fatal strokes with candesartan treatment but failed to show benefit on cognitive function compared with other anti-hypertensive drugs given to the control group [71].

INTERPLAY AMONG THE RAS COMPONENTS

Based on the above review of literature, it is clear that RAS modulation can benefit different neurovascular disorders through myriad pleiotropic effects (Figure 3). Furthermore, different interventions in RAS can achieve similar beneficial effects. The reasons for this similarity are multi-fold and can be explained by the following. (1) the RAS represents an integrated system with interconnected components. Ang peptides can be converted into one another through different enzymes. Thus, an increase or decrease in one of the Ang peptides may result in a compensatory change in other peptides levels as well. (2) Ang peptides together with RAS pharmacological agonists/antagonists can bind with modest affinities to receptors other than the ones they are specific for, especially at higher doses [128]. That is why it is very important to determine the dose needed to elicit a certain RAS component modulation without affecting the others. (3) It has also been shown that stimulating one of the RAS components can result in modulation in the gene transcription and translation of other system components. (4) Interactions between different Ang receptors have also been suggested. Both AT2R and Mas receptors have been reported to dimerize with the AT1R and inhibit its signalling [202,203]). Dimerization of AT2 and Mas receptors has been shown recently [204] and could explain the functional inhibition of either receptor by blocking the other in many studies. In experimental stroke, both the AT2R antagonist, PD123319, and the Mas receptor antagonist, A-799, were shown to block the neuroprotection and behavioural improvement of Ang-(1–7) and C21 [205]. Despite this overlap in actions among RAS components, differences in the outcomes of targeting each individual component still exist. Therefore, a thorough consideration of the different actions of the RAS components should be taken before selecting which RAS component to be targeted in different CNS disorders clinically. Taking the central effect on BP after stroke as an example, whereas post-stroke AT1R blockade is associated with BP reduction, AT2R or Mas receptor stimulation seems to not affect the BP experimentally at least at the doses discussed above. The three interventions have been shown to improve experimental stroke outcome. However, we now know that BP lowering could decrease brain perfusion in some stroke patients and an agent with no effect on BP would more likely reach the clinic as an acute ischaemic stroke treatment.

The pleiotropic therapeutic actions of the RAS in neurovascular disorders

Figure 3
The pleiotropic therapeutic actions of the RAS in neurovascular disorders
Figure 3
The pleiotropic therapeutic actions of the RAS in neurovascular disorders

TRANSLATING PRECLINICAL ANGIOTENSIN SYSTEM MODULATORS TO THE CLINICAL SETTING

Despite the large body of literature documenting the benefits of RAS modulation in experimental models of brain/retinal disorders, this is not reflected in the clinical setting. The reasons behind this translational gap are multifactorial. First, the translational failure could be partially attributed to differences in the pathology and mechanisms of disease in rodents compared with humans. This highlights the need to test new therapeutics in more clinically relevant animal models and meaningful end-points. Second, experimental studies adopt genetic approaches, non-druggable compounds or use clinically irrelevant routes of administration to bypass the BBB or retinal barrier such as ICV injections. While these studies are very important to advance our knowledge, they should be accompanied with parallel efforts to identify new druggable tactics that modulate the newly identified molecular targets, as well as pharmaceutical formulations that traverse the CNS barriers and provide sustained drug availability. Third, there is usually a difference in time window of intervention in pre-clinical studies compared with clinical trials. Whereas experimental studies usually employ preventive or early interventions, this is more difficult to achieve in a clinical setting. For instance, stroke patients often present late in the emergency department whereas most retinopathy patients seek medical help when the disease has well progressed. Lastly, heterogeneity and associated multiple comorbidities in patients recruited in the clinic does not match the animal studies that are usually conducted in a homogeneous strain of rodents that are young and otherwise healthy or have one controlled comorbidity. One striking example is the recent analysis of data from SCAST trial that showed benefit with BP lowering with candesartan in patients with large infarcts but not in those with lacunar stroke [206]. These results echoed previous data from the Intravenous Nimodipine West European Stroke Trial (INWEST) that showed worsened outcome with nimodipine treatment in lacunar stroke patients [207]. The authors suggested that this difference could be due to a long-standing high BP in lacunar stroke patients that make them more sensitive to BP lowering and subsequent brain hypoperfusion. On the other hand, patients with large infarcts are more susceptible to oedema and haemorrhagic transformation that would probably benefit from moderate BP lowering. In our hands, a hypotensive dose of candesartan could improve functional outcome and reduce oedema and haemorrhagic transformation in animals with large strokes and no comorbidities. Collectively, to translate RAS modulators to the clinic, it is imperative to test new therapies in different rodent disease models with different comorbidities as well as female and aged animals. Based on the pre-clinical results, clinical trials should be designed to dissect the treatment outcome based on patients and disease stratification.

CONCLUSION

Overwhelming experimental data show that modulation of the RAS by inhibition of the Ang II/AT1R axis or stimulation of the protective axes, AT2R/Ang-(1–7)/Mas or Ang IV/AT4R achieves beneficial outcomes on different neurovascular and visual disorders beyond BP reduction. Given the different pathophysiologies underlying these disorders, identification of the best approach to modulate RAS in each disease condition is important to further proceed to the clinic. Extensive experimental studies followed by rigorous clinical trials should be conducted to explore the potential use of ACEI and ARBs in neurovascular disorders and translate pre-clinical RAS modulating drugs to the clinic, thus reaping the benefits of the RAS.

FUNDING

This work was supported by the Veterans Affairs Merit Review (BX000891) and (RO1-NS063965); and the Jowdy and Distinguished Research Professorship (to S.C.F.) and R01-EY-022408 (to A.B.E.).

Abbreviations

     
  • ACE

    angiotensin-converting enzyme

  •  
  • ACEI

    angiotensin-converting enzyme inhibitors

  •  
  • AD

    Alzheimer’s disease

  •  
  • AGE

    advanced glycation end products

  •  
  • Ang

    angiotensin

  •  
  • ARB

    angiotensin type 1 receptor blocker

  •  
  • AT1R/AT2R

    angiotensin II type 1/2 receptor

  •  
  • BBB

    blood–brain barrier

  •  
  • BDNF

    brain derived neurotrophic factor

  •  
  • BP

    blood pressure

  •  
  • C21

    compound 21

  •  
  • CA

    cerebral aneurysms

  •  
  • CBF

    cerebral blood flow

  •  
  • CNS

    central nervous system

  •  
  • DIRECT

    DIabetic REtinopathy Candesartan Trial

  •  
  • DR

    diabetic retinopathy

  •  
  • eNOS

    endothelial nitric oxide synthase

  •  
  • HA

    heat acclimation

  •  
  • i.p.

    intraperitoneal

  •  
  • ICH

    intracerebral haemorrhage

  •  
  • ICV

    intracerebroventricular

  •  
  • INTERACT

    Intensive blood pressure reduction in acute cerebral haemorrhage trial

  •  
  • INWEST

    Intravenous Nimodipine West European Stroke Trial

  •  
  • IRAP

    insulin regulated aminopeptidase

  •  
  • KO

    knockout

  •  
  • LDH

    lactate dehydrogenase

  •  
  • MCA

    middle cerebral artery

  •  
  • MCAO

    middle cerebral artery occlusion

  •  
  • NEJM

    New England Journal of Medicine

  •  
  • OGD

    oxygen glucose deprivation

  •  
  • pMCAO

    permanent middle cerebral artery occlusion

  •  
  • PPAR-γ

    peroxisome proliferator-activated receptor γ

  •  
  • PROGRESS

    The perindopril protection against recurrent stroke study

  •  
  • RAGE

    receptor for AGE

  •  
  • RAS

    renin–angiotensin system

  •  
  • ROP

    retinopathy of prematurity

  •  
  • ROS

    reactive oxygen species

  •  
  • SAH

    subarachnoid haemorrhage

  •  
  • SCAST

    Scandinavian Candesartan Acute Stroke Trial

  •  
  • SCOPE

    Study on COgnition and Prognosis in the Elderly

  •  
  • SHR

    spontaneously hypertensive rat

  •  
  • STZ

    streptozotocin

  •  
  • TBI

    traumatic brain injury

  •  
  • tPA

    tissue plasminogen activator

  •  
  • VEGF

    vascular endothelial growth factor

  •  
  • WT

    wild-type

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