Camici, Giovanni G.

Sessa, Maria

Spescha, Remo D.

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EDITORIALAngiopoietin-like 4 and ischaemic stroke:a promising startRemo D. Spescha1, Maria Sessa2, and Giovanni G. Camici1*1Cardiovascular Research, Physiology Institute, and Center for Integrative Human Physiology (ZHIP), University of Zurich, Switzerland; and 2Department of Neurology, San RaffaeleScientific Institute, Milan, ItalyOnline publish-ahead-of-print 31 May 2013This editorial refers to ‘Protective effects of angiopoietin-like 4 on cerebrovascular and functional damages in ischae-mic stroke,†’ by C. Bouleti et al., on page 3657Stroke is a global cause of morbidity and mortality, ranking fourthamong all causes of death.1 Although considerable progress hasbeen made in developing effective tools for acute stroke treatment,at present the only drug approved is recombinant tissue plasminogenactivator (rt-PA); thus, new strategies for its effective prevention andtreatment are essential. Following ischaemia/reperfusion, theblood–brain barrier (BBB) becomes more permeable and, in doingso, it promotes an increased infiltration of pro-inflammatory cells,resulting in the so-called ‘reperfusion injury’.2Given its key role inme-diating ischaemia/reperfusion-related neuronal damage, the BBB is acentral target for the development of novel therapeutical strategies.Bouleti and colleagues have provided an elegant study reporting anew target improving stroke outcome in mice.3 Their study showsthat angiopoietin-like 4 (ANGPTL4) modulates endothelial perme-ability following ischaemia/reperfusion and thus represents a poten-tial new therapeutical target for the treatment of stroke.ANGPTL4, first discovered in 2000, was originally classified as anadipokine playing roles in lipid metabolism.4 Over the last decade,ANGPTL4has been recognized toplayadditional roles in tumorigen-esis, angiogenesis, and redox regulation.4 Bouleti and colleaguesinvestigated the role of ANGPTL4 in stroke by using a transientfocal cerebral ischaemia murine model, where the middle cerebralartery was occluded for 1 h, followed by 24 h of reperfusion.Indeed, they could show that recombinant human ANGPTL4(rhANGPTL4) treatment prior to the ischaemic episode greatlyreduced the stroke size and consequent neurological deficit. Toprovide additional supporting evidence for the protective effects ofANGPTL4, Bouleti et al. analysed stroke outcome in ANGPTL4knockout mice undergoing ischaemic stroke. Moreover, to translatetheir findings into a more clinically relevant experimental set-up, theauthors treated mice with rhANGPTL4 upon reperfusion, 1 h afterthe ischaemic event. Both in ANGPTL4 knockout mice and in thepost-ischaemic rhANGPTL4-treated mice, the authors couldconfirm the protective effects of ANGPTL4 on stroke. Finally, totest the responsiveness of ANGPTL4 to stroke also in humans,Bouleti et al. stained brain samples of patients who had previouslydied from ischaemic stroke and demonstrated an increased expres-sion of ANGPTL4.Given the key role of vascular integrity in determining strokeoutcome,2Bouleti andcolleagues focusedonanalysingendothelial net-works to characterize theprotective effects of rhANGPTL4 treatmenton stroke outcome. They demonstrated an improved endothelialnetwork after ischaemia/reperfusion brain injury in the rhANGPTL4-treated mice as compared with controls, indicating a preservation ofthe vasculature during stroke. Cerebral endothelial cells build theinitial barrier of the BBB separating blood components from braincells, andareconnectedby tight andadherens junctionproteins.5Adis-ruption of these cell–cell contacts leads to vascular leakage, oedemaformation, and brain damage. In the present work, the integrity oftight and adherens junctions was assessed by characterizing claudin-5and VE-cadherin, two main junction proteins.5 The authors showedan increase in claudin-5- and VE-cadherin-positive areas after ischae-mia/reperfusion injury in the rhANGPTL4-treated mice comparedwith the control mice, indicating an effect of ANGPTL4 on preservingthe integrity of tight and adherens junctions in stroke.Acutely, vascular endothelial growth factor (VEGF) is a potentme-diatorof vascular permeability, and its antagonismhas been shown toreduce ischaemia/reperfusion-related brain oedema and injury.6Given the important role of VEGF as a mediator of acute vascularleakage following ischaemia7 (Figure 1), Bouleti et al. tested the possi-bility that rhANGPTL4 treatmentmay act by disrupting VEGF recep-tor 2 (VEGFR2) signalling. Indeed, they showed that ANGPTL4maintains vascular integrity via inhibition of VEGF-induced, VEGFR2-mediated, disruption of VE-cadherin and claudin-5; a process in turndepending on Src phosphorylation and phosphoinositid-3 kinase(PI3K)/Akt activation (Figure 1).* Corresponding author. Cardiovascular Research, Physiology Institute, University of Zurich and Cardiology, Cardiovascular Center, University Hospital Zurich, Winterthurerstrasse190, 8057 Zu¨rich, Switzerland. Tel +41 44 635 64 69, Fax: +41 44 635 68 27, Email: Giovanni.camici@uzh.chThe opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.† doi:10.1093/eurheartj/eht153.Published on behalf of the European Society of Cardiology. All rights reserved.& The Author 2013. For permissions please email: journals.permissions@oup.comEuropean Heart Journal (2013) 34, 3603–3605doi:10.1093/eurheartj/eht183Transmigration of circulating cells from the vasculature into thebrain is a key step in tissue damage following ischaemia/reperfusioninjury. This event is promoted, in part, by an up-regulation of endo-thelial adhesion molecules. Bouleti and colleagues demonstratedthat rhANGPTL4 treatment reduces intercellular adhesionmolecule-1 (ICAM-1) expression in the ipsilateral hemisphere ofrhANGPTL4-treated mice as compared with controls, indicatingthat ANGPTL4 may also interfere with inflammatory responses fol-lowing ischaemia/reperfusion.In the clinical setting, rt-PA was first approved by the Food andDrug Administration (FDA) in 2006 for the treatment of ischaemicstroke within 3 h from symptom onset, after the publication of theNINDS trial,8 in which a 12% absolute (32% relative) increase inthe number of patients with minimal or no disability was achievedin the rt-PA group compared with placebo. However, access tort-PA is limited by numerous contraindications, which make thistreatment available only for a minority of patients. In addition,rt-PA treatment is burdened by a major complication, i.e. haemor-rhagic evolution of the ischaemic lesion, which is one of the principalreasons given by many emergency room physicians and neurologistsfor their avoidance of use of rt-PA therapy.In their study, Bouleti et al. demonstrate that administration ofANGPTL4 in an ischaemic stroke model decreases infarct size andimproves neurological function by maintaining vascular integritythrough prevention of BBB breakdown.From a clinical perspective, these data are very interesting, as wedo know that BBB breakdown is involved in both ischaemic and haem-orrhagic stroke, as well as in the haemorrhagic transformation of is-chaemic stroke, either spontaneously or after rt-PA administration.However, even if numerous neuroprotective agents have alreadybeen shown to be effective in ameliorating outcome in experimentalmodels of stroke, to date clinical neurologists are facedwith a long listof failures in the translation into the clinical setting. To address thisissue, the Stroke Therapy Academic Industry Roundtable (STAIR)published in 1999 recommendations to improve the quality of pre-clinical studies of acute stroke therapies,9 further updated in2009.10 These guidelines include, first of all, methodological stan-dards, such as random allocation, allocation concealment, samplesize calculation, inclusion and exclusion criteria, randomization,reporting of animals excluded from analysis, and blinded assessmentof outcome, as well as reporting of potential conflicts of interest andstudy funding. In addition, the authors underline the intrinsic limita-tions of animal strokemodels, themost relevant being that ischaemiais experimentally induced in otherwise healthy animals, whereashuman stroke occurs in the context of different risks factors and con-comitantmedications. Finally, accumulating data suggest thatmanyofthe neuroprotective targets tested in preclinical models may have anegative effect on the recovery process. Thus, any acute therapymust consider whether the desired target plays a role in the subse-quent process of recovery. Accordingly, multiple endpoints, suchas histological endpoints, biologicalmarkers, imaging data, andbehav-ioural and functional outcomes, should be carefully identified andtested at the appropriate time points. In line with these considera-tions, many of the animal models demonstrated optimal benefit in atime frame that was not practical for clinical stroke intervention,such as either pre-treatment or within 90 min of the infarction.Because the onset-to-needle time in the real world is relatively long,the timewindow in animal experiments shouldbe defined accordingly.Bouleti and colleagues showvery convincingly and indetail the vas-culoprotective properties of ANGPTL4 in ischaemic stroke. In par-ticular, the post-ischaemic treatment with rhANGPTL4 providesclinical relevance and sets the basis for follow-up investigations.However, there are also some limitations to this work, whichshould be mentioned. First of all, all analyses concerning strokesize, neurological deficit, and mechanisms are performed at shorttime points and no data are provided to confirm the protectiveeffects of rhANGPTL4 treatment beyond 24 h. Given the known bi-phasic nature of some of the molecular signals activated duringstroke, the role of ANGPTL4 in vascular integrity and strokeoutcome should also be studied long term to elucidate fully its thera-peutic potential. Secondly, most in vitro experiments are conductedon human endothelial cells of venous or dermal origin while wefeel that mechanistic studies should also be confirmed on humanendothelial cells originating from cerebral arteries to excludepossible cell type-specific effects.Recently, stroke research reached beyond the role of the BBB;indeed, a number of other approaches have also been considered.Free radicals are important mediators of BBB damage followingischaemia; thus, different strategies to prevent the surge of reactiveoxygen species have been successfully studied.11,12 Additionally,much focus has also been put on studying the therapeutic potentialof stem cell transplantation in stroke patients. Although its effective-ness in stroke animalmodels13 as well as its clinical safety and feasibil-ity were demonstrated,14 the clinical efficacy of stem cell therapy stillhas to be improved15 so as to become a concrete therapeutic alter-native, and at present this scenario still seems far away.Figure 1 Schematic representation of the molecular mechan-isms activated in response to ischaemia and downstream ofVEGFR2 involving Src, PI3-Akt and ANGPTL4, ultimately leadingto disruption of VE-cadherin and claudin-5.Editorial3604Wedo hope that, if the results obtained by Bouleti and colleaguesare confirmed by further experiments adhering to the suggestedrecommendations, any clinical trial implemented will not run intopreviously observed trivialities. The world outside desperatelyneeds effective new therapies to combat stroke, which every yearcauses millions of people to become disabled, and is likely to causeeven more with the ageing population.Conflict of interest: none declared.References1. Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, BordenWB, Bravata DM,Dai S, Ford ES, Fox CS, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ,Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Makuc DM,Marcus GM, Marelli A, Matchar DB, Moy CS, Mozaffarian D, Mussolino ME,Nichol G, Paynter NP, Soliman EZ, Sorlie PD, Sotoodehnia N, Turan TN, Virani SS,Wong ND, Woo D, Turner MB. Heart disease and stroke statistics—2012 update:a report from the American Heart Association. Circulation 2012;125:e2–e220.2. Eltzschig HK, Eckle T. Ischemia and reperfusion—from mechanism to translation.Nat Med 2011;17:1391–1401.3. Bouleti C, Mathivet T, Coqueran B, Serfaty J-M, Lesage M, Berland E, Ardidie-Robouant C, Kauffenstein G, Henrion D, Lapergue B, Mazighi M, Duyckaerts C,Thurston G, Valenzuela DM, Murphy AJ, Yancopoulos GD, Monnot C, Margaill I,Germain S. Protectiveeffectsof angiopoietin-like4oncerebrovascular and function-al damage in ischaemic stroke. Eur Heart J 2013;34:3657–3668.4. Zhu P, Goh YY, Chin HF, Kersten S, Tan NS. Angiopoietin-like 4: a decade of re-search. Biosci Rep 2012;32:211–219.5. Zlokovic BV. The blood–brain barrier in health and chronic neurodegenerative dis-orders. Neuron 2008;57:178–201.6. van BruggenN, ThibodeauxH, Palmer JT, LeeWP, Fu L, Cairns B, TumasD,Gerlai R,Williams SP, van Lookeren Campagne M, Ferrara N. VEGF antagonism reducesedema formation and tissue damage after ischemia/reperfusion injury in themouse brain. J Clin Invest 1999;104:1613–1620.7. Weis S, Shintani S, Weber A, Kirchmair R, Wood M, Cravens A, McSharry H,Iwakura A, Yoon YS, Himes N, Burstein D, Doukas J, Soll R, Losordo D,Cheresh D. Src blockade stabilizes a Flk/cadherin complex, reducing edemaand tissue injury following myocardial infarction. J Clin Invest 2004;113:885–894.8. Tissue plasminogen activator for acute ischemic stroke. The National Institute ofNeurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995;333:1581–1587.9. Recommendations for standards regarding preclinical neuroprotective and restora-tive drug development. Stroke 1999;30:2752–2758.10. Fisher M, Feuerstein G, Howells DW,Hurn PD, Kent TA, Savitz SI, Lo EH. Update ofthe stroke therapy academic industry roundtable preclinical recommendations.Stroke 2009;40:2244–2250.11. Zhang P, LiW, Li L,Wang N, Li X, GaoM, Zheng J, Lei S, Chen X, Lu H, Liu Y. Treat-ment with edaravone attenuates ischemic brain injury and inhibits neurogenesis inthe subventricular zone of adult rats after focal cerebral ischemia and reperfusioninjury. Neuroscience 2012;201:297–306.12. Spescha RD, Shi Y, Wegener S, Keller S, Weber B, Wyss MM, Lauinger N,Tabatabai G, Paneni F, Cosentino F, Hock C, Weller M, Nitsch RM, Luscher TF,Camici GG. Deletion of the ageing gene p66Shc reduces early stroke size followingischaemia/reperfusion brain injury. Eur Heart J 2013:34:96–103.13. van Velthoven CT, Sheldon RA, Kavelaars A, Derugin N, Vexler ZS, Willemen HL,MaasM,HeijnenCJ, FerrieroDM.Mesenchymal stemcell transplantation attenuatesbrain injury after neonatal stroke. Stroke 2013;44:1426–1432.14. Bhasin A, Padma Srivastava MV, Mohanty S, Bhatia R, Kumaran SS, Bose S. Stem celltherapy: a clinical trial of stroke. Clin Neurol Neurosurg. 2012;in press.15. Misra V, Ritchie MM, Stone LL, LowWC, Janardhan V. Stem cell therapy in ischemicstroke: role of IV and intra-arterial therapy. Neurology 2012;79(13 Suppl 1):S207–S212.Editorial 3605

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