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REVIEWOpenAccessAngiogenesisinold-agedsubjectsafterischemicstroke:acautionarynoteforinvestigatorsEugenBPetcu1*,RobertASmith1,RodicaIMiroiu2,MariaMOpris3AbstractAngiogenesisrepresentsaformofneovascularisationofexceptionalimportanceinnumerouspathologicalconditionsincludingstroke.
Inthiscontextitisdirectlyrelatedtoneuroregenerationwhichisseenincloseproxi-mity.
However,numerousexperimentaldatahavebeendrawnfromstudiesthathaveignoredtheagecriterion.
Thisisextremelyimportantasangiogenesisisdifferentinyoungversusoldsubjects.
Extrapolatingdataobtainedfromstudiesperformedinyoungsubjectsor"invitro"toold-agepatientscouldleadtoinexactconclusionssincethedynamicsofangiogenesisisage-dependent.
Thecurrentreviewcoversthekeyfeaturesofbrainsenescenceincludingmorphologicalandfunctionalchangesrelatedtothebrainparenchyma,itsvascularnetworkandbloodflowwhichcouldpossiblyinfluencetheprocessofangiogenesis.
Thisisfollowedbyadescriptionofpost-strokeangiogenesisanditsrelationshiptoneuroregen-erationanditsmodulationbyvascularendothelialgrowthfactor(VEGF)andinsulin-likegrowthfactor1(IGF1),themostimportantfactorsactiveinoldbrainafterischemicinjury.
IntroductionNeovascularizationrepresentsacrucialphenomenonofparamountimportancefortheclinicaloutcomeinvar-iouspathologicalconditionsincludingcancer,myocar-dialinfarctionandcerebralstroke.
Untilnottoolongago,itwasthoughtthatCNSdamageinducedbystrokeisassociatedwithirreversibletissuedamage.
However,recently,experimentaldataindicatesthatthisisnotthecaseandneuroregenerationisobservedafterstroke[1,2].
Interestingly,itappearsthatpost-strokeneurore-generationdependssignificantlyonneovascularizationwhichisencounteredinseveralflavors:vasculogenesis,angiogenesisandarteriogenesis[3].
Vasculogenesisrepresentstheembryologicaldevelopmentofthebloodvesselsfromangioblasticprecursorsandithasbeenrecentlydescribedinpatientsafterstroke[4].
Although,theextenttowhichvasculogenesismodulatespost-strokeneuroregenerationisnotknown,thelinkbetweenthisprocessandangiogenesisisrepresentedbyVEGFanditsreceptor,whichmodulatetransformationofimmatureprecursorstructuresintomaturecapillaries[5].
Arteriogenesisisthegrowthofcollateralarteriesfrompre-existingarteriolesafterblockageofthemainartery.
Comparedwithangiogenesisitdoesnotrequireahypoxicenvironment,andistypicallyactivatedbyincreasedpressureandstress,suchasthatcausedbyoccludedandpartiallyoccludedvessels[6].
Thecontri-butionofthisprocesstoneuroregenerationisunknown,however,numerousstudieshavereportedthatangiogen-esisorformationofnewcapillariesfrompre-existentvesselsiscloselyrelatedtoneuroregeneration.
Afterstroke,primordialcellscapabletodifferentiateintofunctionalneuronshavebeenidentifiedintheimmedi-atevicinityofnewlyformedcapillaries[7].
Therefore,itwasclaimedthatthisprocesscanberegardedasaneu-rorestorativeeventpromotingformationofnewneuronsfromadultbrain'sownneuralstemcells(NSC)[8,9].
Althoughfactorssuchasmatrixmetalloproteinase-2(MMP-2),matrixmetalloproteinase-9(MMP-9),tissueinhibitorofmatrixmetalloproteinase1(TIMP-1),Hepa-tocytegrowthfactor(HGF-alpha),monocytechemo-attractantprotein1(MCP-1)areincreasedafterischemicstrokethemostimportantseemstobeVEGFanditsreceptorwhichareincreasedintheperipheryoftheischemiczoneat3hoursafterstroke[10,11].
Although,agreatdealofresearchhasbeenperformed,itseemsthattherearesignificantdifferencesintheangiogenesisencounteredinoldsubjectscomparedwith*Correspondence:e.
petcu@griffith.
edu.
au1GriffithUniversitySchoolofMedicine,GoldCoastCampus,GriffithUniversity,QLD4222,AustraliaFulllistofauthorinformationisavailableattheendofthearticlePetcuetal.
JournalofAngiogenesisResearch2010,2:26http://www.
jangiogenesis.
com/content/2/1/26JOURNALOFANGIOGENESISRESEARCH2010Petcuetal;licenseeBioMedCentralLtd.
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youngones,includingtheextentofthisprocessandthefactorsthatmaymodulateitduringdifferentdevelop-mentalstages.
However,sinceangiogenesisdependsonthepre-existingvascularnetworkitisveryimportanttounderstandifthereisanyrelationshipbetweenwhatishappeningwiththebrainperseanditscerebralbloodvesselsduringsenescenceandtheextentand/ormodu-lationofpost-strokeangiogenesisinthiscontext.
Thecurrentreviewwillhighlightthemostsalientpointsrelatedtothesenescentbrainanditsvasculature,andthenbasedonthepublisheddatawewillreviewthefactorswhichunequivocallymodulateangiogenesisonlyinelderlysubjects.
Thisisnecessarysinceischemicstrokeismostlydescribedinoldageandextrapolatingresultsobtained"invitro"orfromyoungsubjectscouldleadtoerroneousconclusions.
CNSagingprocess:pivotalpointsNormalagingisassociatedwithacognitivedeclineandunderstandingtherelatedmechanismsremainsacentralchallengeinneuroscience.
Moreover,itiscurrentlypoorlyunderstoodhowtheCNSmorphologicalchangesassociatedwitholdagewouldaffectthevascularnet-workandultimatelypost-strokeangiogenesis.
Morphologicalandphysiologicalstudieshavetriedtoexplainthedeclineincognitivefunctionassociatedwitholdagebasedonanatomicalchanges.
Morethanfiftyyearsago,itwassuggestedthatweightreductioninthesenescentbraincouldbeexplainedbyasignificantreductionintheneurons[12].
Recently,MRIstudiesconductedinhealthyvolunteershaverevealedthatbrainweightlossmayaffectwithpredilectiononlysomeregionsofthebrainsuchashippocampusorthepre-frontal,frontalorenthorinalcortexandthelossofwhitematterisgreaterthanthedecreaseingreymatter[13,14].
Otherauthorshaverecordedareductionofthewholelimbicsystemgreymatterinhealthyelderly[15].
Between30and90yearsofage,thereisanoveralldecreaseinweightof14%recordedinthecerebralcortexassociatedwitha35%reductioninthehippocampus,anda26%weightlossinthecerebralwhitematter[13].
How-ever,itisstilldebatableifthechangesseeninhippocam-pusarerelatedto"normal"senescenceasotherstudieshavesuggestedthatcelldeathandadeclineinweightoccurringinthisregionisnotnormallyobserved[16,17].
Studiesinmicehaveindicatedthatagingmayreducebothoverallneuralcellproliferationaswellasthedevel-opmentalpathwayfollowedbyproliferatingcellsinthebrain,leadingtofewermatureneuronsreplacingthoselosttoageordamage[18].
Regardingthevasculature,althoughearlierstudieshaveshownnodifferenceorevenanincreaseinthecer-ebralarteriolarnetworkinoldversusyoungsubjects,thecurrentopinionisthatoldageischaracterizedbyasignificantdecreaseindensityofvesselssupplyingthecerebralcortexcomparedwithyoungcontrolsaswellasmorphologicalchangesoftheremainingvessels[19-22].
Morerecently,Amentaetal(1995)havereportedthatthecapillarynetworkissignificantlydecreasedinWistarratsof27and24monthsversusyoung12month-oldsubjects[23].
Therefore,itseemsunequivocalthatagingisassociatedwithasignificantdecreaseinsuperficialcorticalvesselswhichaccordingtosomeauthors,couldbeinducedbyanage-relateddecreaseingrowthhor-moneandinsulin-likegrowthfactor1[21].
However,growthhormonetreatmentadministeredtoagedani-malsfor6weeksdidnotalterhippocampalcapillarydensityanddidnotamelioratetheage-relateddeficitinangiogenesis.
Therefore,theexactrelationshipbetweengrowthhormoneandangiogenesisremainstobeeluci-dated.
However,agedanimalsdemonstrateasignificantimpairmentinhypoxia-inducedcapillaryangiogenesiscomparedtoyounganimals[24].
Regardingthestructuralalterationsofthevessels,significantaging-relatedmicrovasculardegenerationwasencounteredespeciallyintheperiventricularwhitematter[25].
Also,inelderlyratsubjectsthereisadecreaseinsmoothmuscleandelastininparallelwithanincreaseincollagenswhichimpairdistension[26].
Senescentarteriolespresentwithalterationsincapil-laryendothelialcellsincludingathickenedbasementmembrane,abnormalinclusionsandabnormalitiesoftheastrocyticendfeet[27-29].
However,themechan-ismbehindthesechangesremainspoorlyunderstoodalthoughitisacceptedthattheseultrastructuralaltera-tionscouldleadtoasmallleakageofbloodinthepar-enchyma[30].
Regardingthecerebralbloodflowinold-age,recentdatasuggeststhatitdecreaseswithadvancingage[31,32].
Previousstudieshaveshownadirectcorrelationbetweencerebralbloodflowandvasculardensity[33].
Itseemsthatcerebralbloodflowismodulatedbycirculat-ingnorepinephrine,NOandsympatheticnoradrenergicinnervationsofcerebralarteries.
Theyoungsubjectsarecharacterizedbylittlenoradrenergicinnervationsofcere-bralarteriesandweakcerebralvasoconstriction.
Theseinnervationsincreasewithagebutdecreasebymiddle-ageinamurinemodel.
However,thenorepinephrineevokedcerebralvasoconstrictionisstrongerinmatureandmiddle-agedratsandalthoughtheNOwouldlimitthevasoconstriction,thisisfollowedsubsequentlybyadropincerebralbloodflow[34].
Interestingly,previousstudiesconductedinamurinemodelsuggestthatadecreasedbloodflowisparalleledbyadeclineincogni-tivetasks[35-37].
Therefore,onemayspeculatethatadecreaseinbloodflowwouldleadtoadecreasedener-geticsupportforneuronswhichcomplicatesthefunc-tionalprofileoftheagingbrainincludingthepost-strokePetcuetal.
JournalofAngiogenesisResearch2010,2:26http://www.
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com/content/2/1/26Page2of10angiogenesis.
Themostimportantchangesinvasculariza-tionwithageinginthebrainarerepresentedinFigure1.
Inaddition,oldageischaracterizedbythepresenceofseveralpathologicalentitiesaffectingthevasculature.
Cerebralatherosclerosisandsmallvesseldiseasearecharacterizedbyplasmaproteininfusionintothevesselwall,accumulationoffoamycells,andfibrosiswhileanotherrelativelycommoncondition,amyloidangiopa-thy,isassociatedwithdepositionofamyloidintheves-selwall[38].
Therefore,sincethefunctionalityofthenervoussystemisdependentuponawelldevelopedandmaintainedbloodsupply,wecouldspeculatethatanymorphologicalandphysiologicalaging-relatedchangesinthemicrovasculaturecouldaffectneuronalintegrity.
RelatedtoAlzheimer'sdiseasewhichisalsoseeninold-agepatient,clinicalstudieshaveindicatedthateduca-tionhasaprotectiveeffect.
Thishasbeenattributedtoa"reservoireffect",withthelossofneuronscompen-satedforbymoreextensiveneuralconnections.
Giventhelinksbetweendementiasandreducedbloodflowtothebrain,itispossiblethatatleastsomeofthiseffectmaybemediatedthroughamoredevelopedvascularsystem,orpotentiallybyretentionofmorejuvenilemodesofangiogenicresponseduetoextendedlearning.
Thiswouldmakesomesenseinthecontextofexperi-mentalstudiesconductedinrats,whichshowthatangiogenesisoccursintheadultratcerebellumafterphysicalexerciseandmotorskillslearning[39].
Abriefaccountofcentralnervoussystem"normal"senescenceandthepathologicalchangesassociatedwithitispresentedinFigure2.
Post-strokeangiogenesisOnemaydefinetheprocessofangiogenesisassprout-ingofnewcapillariesfrompre-existentvessels.
Asaresultofthisongoingprocess,thenewlyformedplexusincreasesgraduallyinsizeandremodelsintoavascularnetworkwhichultimatelyformsendothelial-cell(EC)channelsincloseproximitywithpericytesandsmoothmusclecells.
Thiscellularcompositionisofparamountimportanceforfunctionalityofthenewvesselsinclud-ingthestrengthofthewallandregulationofthebloodflow[40].
Interestinglyafterstroke,neuroblastswhichwillfurtherdifferentiateintofullyfunctionalneuronswereidentifiedincloseproximityaroundtheimmaturenewlycreatedvascularnetwork[41].
Thiswouldsuggestthatneurogenesisdependsonapreli-minaryangiogenesis.
Post-strokecerebralangiogenesisrepresentsanessen-tialeventofcrucialimportancethatunfortunatelyisnotcompletelyunderstood.
Severalfactorssuchas:beta-Figure1Agingproducesanumberofphysicalandbiochemicalchangesinthevascularsystemthatcontributetotheagerelateddegenerationofthebrain.
Atthemacroscopiclevel,reducedvesseldensityisobservedinagingbrains,leadingtoanoverallreducedbloodflowandoxygenationintobraintissue,thatmaybefurtherexacerbatedbypathologicalfactors.
Atthecellularlevel,thevesselwallsbegintoreducetheexpressionofgrowthfactorreceptors,leadingtoreducedabilitytorespondtogrowthandsurvivalfactors.
Vesselsalsobegintolosesmoothmusclecells,reducingthecapacityofvesselstomaintainbloodpressure,reducingoxygenationincertaincircumstances.
Agingalsoleadstoareducedexpressionofgrowthandsurvivalfactorsintothebloodstream,furtherreducingthesurvivalcapacityofvesselliningcells.
Manyofthesefactorscombinetoleadtovesseldegeneration,wherereducedflowrates,reducedreceptorexpressionandreducedgrowthfactorsleadtonarrowingofvessels,furtherreducingflowandreducingvesseldiameter,toapointwhereredbloodcellscannolongerflowthroughvessels,leadingtolossofoxygenationoftissuesandfurtherdegenerationintoastringvesselstate.
Figure2Centralnervoussystem"normal"senescenceandpathologicalchanges.
AgingintheCNSinvolvesarangeofdiversechanges,includingthoseassociatedwithnormalsenescenceandpresentinallsurveyedbrains.
Theseincludereducedweightofbrainasaresultofdecreasedneuroncounts,aswellasreducedvesseldensityandintegrityinthevasculature.
Morepathologicalchangesincludeatherosclerosis,smallvesseldiseaseandamyloidproteins.
Thesecombinewithnormalvaso-constrictionanddilationeffectstoalteroverallcerebralbloodflow.
Petcuetal.
JournalofAngiogenesisResearch2010,2:26http://www.
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com/content/2/1/26Page3of10catenin,matrixmetalloproteinase-2(MMP-2)matrixmetalloproteinase-9(MMP-9),tissueinhibitorofmatrixmetalloproteinase-1(TIMP-1),hepatocytegrowthfac-tor-alpha(HGF-alpha),monocytechemoatractantpro-tein-1(MCP-1)andAngiopoietin1/Tie-2aswellasc-kitareincreasedafterischemicstroke[42].
Beta-cateninisamemberofthecadherincomplexandasignalingproteinintheWntpathway.
Ithasbeenlinkedtotheproliferationofneuronalprogenitorcellsinstrokeinducedneurogenesis[43].
Instroke,MCP-1isthoughttobeoneofthemajorfactorsinfluencinginfil-trationoftheinfarctregionbyleukocytesandislinkedwithincreasedvolumeoftheinfarctandincreaseddamage[44].
ExperimentaldatasuggeststhatinratswithmiddlecerebralarteryocclusionthelackofMCP-1oritsreceptorCCR-2isassociatedwithasignificantdecreaseinthenumberofmigratingneuroblastsreach-ingtheischemicarea.
Thisaffectstheneuralregenera-tionnegatively[45]TheMMPfamilyparticipatesinthebreakdownofvariousextracellularmatrixproteins,andisassociatedwithwoundhealingandtissueremodeling.
Instroke,theMMPshavebeenimplicatedinthebreakdownoftheblood-brainbarrierandincreaseddamage[46-51].
DifferentMMPsareexpressedindifferentconditionsandatdifferenttimesfollowingstroke,withMMP-2beingamongstthefirstactivated,followedbyMMP-9inlaterstagesofinflammationandrepair[52].
Researchconductedinmurinesrecently,indicatesthatthemajorsourceofMMP-9incerebralischemiaisrepresentedbybone-marrowderivedcells[53].
Remark-ably,MMP-9promotesneuralprogenitorcellsmigrationtowardstheischemicbrainareainamodeloftransgenicmiceafterphotothromboticischemia[54].
ClinicalstudiesconductedinpatientswithvarioustypesofstrokehaverevealedthatMMP-2geneisasso-ciatedwiththedevelopmentoflacunarstroke[55].
However,itrisesinparallelwithMMP-9inaratmodeloftransientcerebralischemia[56].
ItseemsthatMMP-2andMMP-9expressionisdecreasedafterminocyclineadministrationinratswithinducedcerebralischemia.
Thisisassociatedwithadecreasedincidenceofhemor-rhageanddecreaseddegradationofcollagenIVandlamininalphainthebrain.
Overall,theneurologicalout-comeincerebralischemiaisimprovedbyminocyclinethroughMMP-2andMMP-9downregulation[57].
InpatientswithseverestrokebothMMP-2andMMP-9haveastrongassociationwithedemaformationandmidlineshift[58].
TheTIMPsareinhibitorsoftheMMPsandtheirinducedoverexpressionhasbeenshowntoaidinreduc-tionofinfarctsizeandrecoveryinaratmodelofischemia[59].
HGF-alphaisknowntoinduceangiogenesisandhasbeenseentoincreaseinexpressionfollowingMCAOinmousemodels,thoughahighserumleveloftheproteinwasfoundtobeanindependentriskfactorforstrokeinpostmenopausalwomen[60,61].
Experimentalevidencesuggeststhatangiopoietin1(Ang1)anditsendothelialkinase2(Tie2)areup-regu-latedafterstrokebyanitricoxidedonorandsubse-quentlypromoteneuroblastcellmigrationtowardstheischemicarea[62].
InceasedlevelsofAng1/Tie2havebeenrecordedinischemicstrokemodelsaftersimvasta-tintreatmentandinfusionofbonemarrowstromalcells.
Bothtreatmentsresultultimatelyinvascularstabi-lizationandangiogenesis[63,64].
Theabovementionedfactorsareinvolvedineventsofparamountimportancenamely,endothelialcellmigration,tissueremodeling,differentiationandtube-formation,vesselstabilizationandstemcellhomingmechanismsinareasofrevascularization.
Therefore,wecouldspeculatethattherapymodulatingtheirexpressionandtheactivityofthesefactorscouldhelptherecoveryandrestorationofthedamageafterstroke[42].
Severalofthesefactorsarealsoassociatedwitharteriogenesis,anditispossiblethatmultiplesystemsmaycomeintoplayafterstroke,dependingonitsseverity,orthatthereisacertainamountofcross-talkbetweentheangiogenicandarteriogenicsystems.
AconcisesummaryofthepossiblemolecularmechanismsandgeneraleffectsofangiogenesisafterstrokeinelderlysubjectsispresentedinFigure3.
Figure3Possiblemolecularmechanismsandgeneraleffectsofangiogenesisafterstrokeinelderlysubjects.
Strokecausesischemicdamagetothebrain,activatingangiogeneicmechanismsinresponse.
Thedegreeofresponseismodulatedbychangestotheneuralandvascularresponsecausedbyaging,butthegeneralresponseremainssimilar.
Growthfactors,tissueremodelingandinflammatoryproteinsarereleased,leadingtothebuildingofnew,welldevelopedendothelialchannels,whichaidrecovery.
Petcuetal.
JournalofAngiogenesisResearch2010,2:26http://www.
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com/content/2/1/26Page4of10However,atthepresenttime,wedonothaveanyinformationonthedynamicsoftheabovementionedfactorswithaging.
Sinceischemicstrokeismostlikelytobeencounteredinelderly,anypossibletherapyshouldbeverifiedinthecontextofaging.
Thismeanstakingintoconsiderationthelevelofthetargetedfactorsinoldage,theabilityofthevascularandsupportsys-temstorespondtothemandtheintegrityofdown-streamgeneexpressioninthetargetedpathways.
Todate,onlyVEGFandIGF-1havebeenevaluatedasmodulatorsofneovascularisationinoldsubjects.
Post-strokeangiogenesismodulatorsinoldagesubjectsVEGFanditsreceptorsWithoutanydoubt,vascularendothelialgrowthfactor(VEGF)isthemostimportantpromoterofangiogenesissecretedbyendothelialcellsandpericytes[65].
Recentresearchevaluatingtheroleofremnantsofcapillariestheso-calledstringvessels,indicatesthatVEGFrepresentsanendothelialcellssurvivalfactor.
Stringvesselshavebeendescribedinischemiccondi-tionsbutalsoinnormalhumanbrains.
Theyrepresentcapillariesthathavelosttheirendothelialcells.
Itseemsthattheirpresenceisassociatedwithanage-relateddeclineinVEGF[66].
OneofessentialaspectsrelatedtoVEGFisrepre-sentedbythefactthatneurogenesistakesplacenearcerebralcapillarieswherebothVEGFandangiogenesisareup-regulated.
Therefore,itisbelievedthatthatVEGFlinksneurogenesisandangiogenesis[67-69].
Afterischemicstroke,VEGFisdetectedonmicroglialcellsandmacrophagesandalsooncapillarieswithintheperi-ischemiczone,whereapro-angiogeniceffectmaybeidentified.
NotablybothVEGFmRNAandoneofitsreceptors(VEGFR-1)areincreasedintheperipheryoftheischemiczoneat3hoursafterstrokereachingapeakafter24h,andremainingdetectable7dayspoststroke[70].
Therefore,itwasarguedthatanincreasedproductionofVEGFanditsreceptorrepresentaphysio-logicalresponsetoischemiawhichultimatelyaimstopreserveandtorestorethedamagednervoustissue,consistentwiththefunctionsoftheVEGFsysteminothertissues.
Remarkably,experimentsconductedinamurinemodelofmiddlecerebralarteryocclusionhaveindicatedthatapoptosisoftheneuronsinthepenumbraissignifi-cantlydepressedafterthebeginningofangiogenesisanditappearsthatanti-apoptosisisachievedbyVEGFdur-ingangiogenesisviatheinducedexpressionofsurvivininendothelialcells[70,71].
Mostimportantly,theexperimentaldataonVEGFhasbeenpositivelymatchedbyclinicaldata.
Neurons,endothelialcells,andastrocytesinthepenumbrafrompatientsthatdiedafterischemicstrokearecharacterizedbyanincreasedexpressionofVEGFcomparedwithcontralateralareas[72].
Moreover,inpatientswithacuteischemicstrokeserialmeasurementspointedtowardsanincreasedserumlevelofVEGF,whichcorrelatedverywellwithinfarctvolumeandclinicaldisability[73].
InatheroscleroticlesionsVEGFisinducedbyC-reac-tiveprotein(CRP)andsignificanttime-dependentup-regulationofVEGF-AmRNAexpressionanditspro-teinwasrecordedinmonocytesaftertreatmentwithCRP.
ItseemsthatthemostplausiblemechanismforthisisrepresentedbytheactivationofaPI3-kinaseandanextracellularsignalregulatedkinase(ERK)[74,75].
Also,VEGFmodulateshypoxia-inducedCNSangiogenesis[76,77].
Inmiddlecerebralarteryocclusion(MCAO)experiments,theinducedhypoxiarepresentsasignalforactivationofhypoxia-induciblefactorswhichsubse-quentlypromoteexpressionofVEGFanditsreceptorgenes[78].
However,asmentionedabove,hypoxia-indu-cibleangiogenesisisdecreasedwithaging[24].
ThereforeonemayconcludethatVEGFand/oritsreceptorsaredown-regulatedwithaging,and/orthatlongtermeffects,suchaspromotermethylationretardthecapacityofagedcellstorespondtopro-angiogenicsignalsbroughtonbyhypoxia.
Interestingly,inselectedareasofbrainsuchasthehippocampusthereisasignificantdecreaseofVEGFbetweenyoungandmiddleageanimals.
However,thereisnodifferencebetweenmiddleageandelderlysubjects[65,79].
ItappearsthatdecreasedhippocampalVEGFconcentrationinmiddleageisrelatedtonumerouschangesinthecellularsubstratesforVEGF.
Theseabnormalitiesincludereducedproliferationofendothelialcellsincapillariesanddegenerationofendothelialcells,especiallyinthevascularnichesurroundingstem/progenitorcells[67].
Recently,invitroandinvivostudiesconductedbyEmerichetal(2007)haveshownthatchoroidplexusepithelialcellsfromyoungsubjectssecretemoreVEGFandaremetabolicallymoreactivethanthesametypeofcellsfromagedanimals[80].
Moreover,transplantationofchoroidplexusepithelialcellsfromoldsubjectsissig-nificantlylessneuroprotectivethanthetransplantofthesametypeofcellsfromyoungrats[80].
Inaddition,theangiogenicandneurogenicresponsetoadeno-associatedviralvector-VEGFinjectionsisdecreasedintheagedmousebrain[81].
Brainsfrom24montholdmice,com-paredtothoseof3and12montholdmice,inthestudybyGaoetal.
showedreducedexpressionofVEGFR-2,anotherVEGFreceptorcommonlyassociatedwithangiogenicfunctions[81].
Thismayexplainthereducedangiogenicresponseseeninthesebrains.
Inaddition,thebrainsof24montholdmiceshowedlowerlevelsofneuroprogenitorcellsfollowingstrokeandVEGFstimu-lation.
Thus,itmaybethatreductionsinVEGFreceptorexpression,accumulationofsenescencemarkersandPetcuetal.
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com/content/2/1/26Page5of10othermetabolicchangesinendothelialandneuralcellsleadtoreducedproliferativeresponse.
Sincetheactivityofotherpro-angiogenicfactorssuchasplacentalgrowthfactor(PLGF)andneuropilins(NP1andNP2)isdirectlylinkedtothelevelofVEGF/VEGFreceptors,onemayspeculatethattheirlevelcouldalsobeaffectedbytheagingprocess[82-84].
However,nostudieshavebeenspecificallydesignedtoevaluatethesefactorsinagedsubjects.
AsummaryofthepossibleVEGFrelatedmechanismsofpost-strokeangiogenesisinelderlysubjectsisrepre-sentedinFigure4.
Insulin-likegrowthfactorI(IGF-1)Experimentsconductedonhumantissuehaveshownthatincreasedlevelsofinsulin-likegrowthfactorI(IGF-I)andvascularendothelialgrowthfactor(VEGF)areassociatedwithneovascularizationinducedbyretinalischemia[85].
Andersonetal(2002)havesuggestedthatIGF-1inducesneurogenesisfromadult-derivedneuralprecur-sorsinvitroandhassimilareffectsonthehippocampalprogenitorpopulationinvivo[86].
Relativelyrecentresearchhasprovedthatinsulin-likegrowthfactor-I(IGF-I)mayregulateneurogenesisintheagingbrain.
ThisexperimentalhypothesishasbeenderivedfromthefactthatIGF-1influencesneuronalproductionduringdevelopmentand,similartoneurogenesisitself,itdecreaseswitholdage.
Lichtenwalneretal(2001)haveshowedanage-dependentreductioninthenumberofnewlygeneratedcellsintheadultdentatesubgranularproliferativezone[87].
Thiswasparalleledbya60%reductioninthedifferentiationofnewborncellsintoneurons.
Remarkably,restorationofIGF-Ilevelsinsenescentratssignificantlyrestoredneurogenesis,withanapproximatelythree-foldincreaseinneuronalpro-ductionreported.
Therefore,theauthorssuggestthatIGF-Imaysignificantlymodulateneurogenesisinaginghippocampusandthatanage-relateddeclineinIGF-I-dependentneurogenesiscouldcontributetoage-relatedcognitivechanges[87].
ExperimentalstudiesconductedinmurinemodelshaveshownthatvasculatureandmeningesareanimportantsourceofIGF-1forthebrainandthatexpres-sioncontinuesthroughoutlife.
Inaddition,therearenochangesinIGF-1geneexpressionwithagebutIGF-1proteinlevelsdecreasesuggestingthattranslationaldefi-cienciesordeficitsinthetransportofIGF-1throughtheblood-brainbarriercontributetothedeclineinbrainIGF-1withage.
ThiswouldimplythatagingiscorrelatedwithsignificantchangesintheIGF-1axiswhichcausethebrainsenescenceitself[88].
Asmentionedpreviously,thevasculardensityonthesurfaceofthecortexdecreaseswithaging.
Thiscorre-lateswithlowIGF-1plasmalevels,whichwouldsuggestthatIGF-1hasanimportantroleinthedeclineofvas-culardensityassociatedwithaging[21].
Inthehippo-campus,concentrationsofIGF-1decreasesignificantlybetweenyoungandmiddleagedexperimentalanimals.
ThedropinIGF-1levelsisalsorecordedinold-agesubjects.
However,thereisnosignificantdifferencebetweenIGF-1levelsrecordedinmiddle-ageandelderlysubjects[89].
RecentexperimentalresearchhasrevealedthatbothlocalandserumIGF-1modulateangiogenesisafterbraintrauma.
LowIGF-1levelimpairsangiogenesisandpromotesvasculardysfunction[90].
Theseresultscon-firmpreviousdatafromelderlypatientswithischemicstrokewhichhavereportedup-regulatedlevelsofIGF-1inthecontextofawellestablishedangiogenesis[91].
Interestinglyinastudyconductedinelderlypatientswithstroke,serumIGF-1levelsassessedwithin24hoursoftheonsetofstrokeweresignificantlylowerthanlevelsincontrols.
PresumablythesepatientshadlowlevelsofIGF-1beforestroke,thoughthishasnotbeenestablished.
However,lowlevelsofIGF-1werefre-quentlyassociatedwithdeath[92].
OtherstudieshaveshownthathighlevelsofIGF-1beforestrokeareasso-ciatedwithalargerischemicarea[92,93].
TheauthorsspeculatethatahighlevelofIGF-1wouldincreasethesusceptibilitytoischemiaproducedbymiddlecerebralarteryocclusion.
InthiscontextthedamageinducedbyincreasedIGF-1couldbeproducedbyactivationofMAPK[94].
Moreoverinanexperimentalsetting,IGF-1isbeneficialifgivenafterischemiabutnotbeforetheFigure4VEGFandpost-strokeangiogenesisinelderlysubjects.
Morphologicalandmolecularchangesleadtomedialcerebralarteryocculsionandsimilarstatesthatgiverisetofullischemicstroke.
BothocculsionandoutrightstrokeleadtostimulationofVEGFreleasebyaffectedcells,whichdrivestheexpressionofadditionaleffectorproteins,increasesangiogenesis,promotescellsurvivalandneurogenesis,leadingtorecovery.
Agingreducestheactivationofcertainresponses,includingHIF-1aandtheabilityofcellstorespondtoVEGFthroughdownregulationofreceptors,impairingrepairandrecovery.
Petcuetal.
JournalofAngiogenesisResearch2010,2:26http://www.
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com/content/2/1/26Page6of10event[95-97].
Unfortunately,wedonothaveaclearexplanationofthesefactsyet,thoughitmaybethathighlevelsofIGF-1priortostrokemayreducetissueresponsivenessafterwards,duetonegativefeedbackloopsreducingexpressionofdownstreamsignalrecep-tors.
ItisalsopossiblethatahighlevelofIGF-1priortostrokemaybeindicativeofsubstantial,butlow-levelhypoxiainthetissueandthatthealreadystressedneu-ronsarelesslikelytosurviveanischemicevent.
Overall,theroleofIGF-1inmodulatingangiogenesisandvascu-lardevelopmentisstillnotcompletelyelucidated.
FurtherresearchshouldtakeintoconsiderationnotonlytheageofthesubjectsbutalsothedynamicsofIGF-1levelbefore,duringandafterischemicdamageproducedbystroke.
OthergrowthfactorsandcellularstudiesAlthoughVEGFandIGFseemtobethemainactorsinpoststrokeangiogenesis,thereareanumberofotherfactorsinplay.
AswellastherelationshipbetweengeneexpressionandageintheVEGFandIGFsystems,simi-larrelationshipshavebeennotedforfibroblastgrowthfactor(FGF)andtransforminggrowthfactorbeta1(TGFb-1).
AsforVEGF,expressionofFGFisincreasedintheareasurroundingastrokeinhumansubjects[98].
Intheratandporcinemodels,however,anagespeci-ficreductioninFGFreceptorexpressionandsignalinghasbeenobserved,anditseemslikelythatasimilarlossofexpressionisexperiencedinhumanbrains[98-100].
Likewise,TGFb-1ismorehighlyexpressedintheimmediateareaaroundastroke,butisnotsufficientlyincreasedtoaffectmeasurementsofconcentration[73].
Studiesincellcultureshaveindicatedthatlongtermculturedcellsshowreducedcapacitytoformtubesinappropriatecultureconditions,aswellasincreasedmor-phologicalheterogeneity[101].
CellculturemodelsofoldercellsalsoshowsimilarlossesofVEGFexpressiontothoseobservedinolderwholeanimals[79].
Thiswouldindicatethatinbothinvivoandinvitrostudies,therearesignificantalterationsinthebehaviorofagedendothelialcellscomparedtoyoungerones.
InconclusionOldageisassociatedwithavarietyofmorphological,physiologicalandmetabolicfeatureswhichmayalterrecoveryafterstroke.
Thesefeaturescombinenormalagingofbrainwiththeongoingprocessesofneurode-generationandsmallvesseldisease.
Theseworkinsynergytoreducethecapacityofbothneuralandvascu-larcellstorespondtoischaemicinsult,aswellascom-promisingtheirmaintenanceandbasicfunctions.
Oneofthemostimportantchangesisrepresentedbyadecreaseofthenormalcerebralvascularnetwork.
Thismayaffecttheabilityoftheold-agesubjectstomountanadequatepro-angiogenicresponseafteraninsultsuchasstroke.
VEGF/VEGFRandIGF-1representthemostimportantmodulatorsofpostischemicangiogen-esis.
Researchisshowingthatsomeofthechangestothemechanismsbehindtheseeffectsaresimilarinbothneuralandvasculartissues.
However,wecannotbesureifthedecreaseintheirlevelisduetomorphological,physiopathologicalormetabolicchanges,orhowthesemayinteracttocontributetothechangesseenintheagingbrainandvasculature.
Theroleandthepromotersofthesefactorsarealsoincompletelyunderstood,buttheymayberelatedtoage-associatedlossofcellularproliferativeabilityandincreasingnegativeregulationbycellularsenescencemarkers.
Inaddition,sinceischemicstrokeisapathologicalentitymostlikelyencounteredintheelderly,futurestudiesshouldevaluateanypossibletherapeutictargetsrelatedtopostischemicstrokeangiogenesisonlyinagedanimalsorhigherpassageinvitrosystems.
Moreresearchisalsoneededtofullyexplainthemechanismsatworkintheischemicsenes-centbrainwhichmayinfluenceangiogenesisand/orthefinaloutcomeofthesubject.
Thisiscrucialnotonlytounderstandthenatureofstroke,butalsotoprovidethebesttherapeuticresponsewithcurrentmethodsandtodevelopnewtreatmentand,potentially,preventativeoptions.
Authordetails1GriffithUniversitySchoolofMedicine,GoldCoastCampus,GriffithUniversity,QLD4222,Australia.
2UniversitateaNationaladeEducatieFizicasiSportdinBucuresti,FacultateadeKinetotherapie,140ConstantinNoicaStreet,060057Bucuresti,Romania.
3UniversitateadeMediciniFarmacieTrguMure,38Gh.
MarinescuStreet540000TrguMure,Romania.
Authors'contributionsEBPhasmadesubstantialcontributionstoconception,design,andinterpretationofdataforthisstudyincludingthedraftingofthemanuscriptandrevisingitcriticallyforimportantintellectualcontentandhasgiventhefinalapprovalfortheversiontobepublished.
RAShasmadesubstantialcontributionstointerpretationofdataforthisstudyincludingthedraftingofthemanuscriptanditsfiguresrevisingitcriticallyforimportantintellectualcontentandhasgiventhefinalapprovalfortheversiontobepublished.
RIMhasmadesubstantialcontributionstoconceptionandinterpretationofdataforthisstudyincludingthedraftingofthemanuscriptandrevisingitcriticallyforimportantintellectualcontentandhasgiventhefinalapprovalfortheversiontobepublished.
MMOhasmadesubstantialcontributionstointerpretationofdataforthisstudyincludingthedraftingofthemanuscriptandrevisingitcriticallyforimportantintellectualcontentandhasgiventhefinalapprovalfortheversiontobepublished.
Authors'informationEBP,MD,MHSc(Pharmacology),PhD(Neurobiology)isanacademicanatomicpathologist,currentlySeniorLecturerwithtrainingandexperienceinNeurobiologyresearchfocusingonmolecularmechanismsofrecoveryafterischemicstroke.
Heconductsanewlycreatedneurobiologyresearchgroupathisinstitution.
RAS,BSc(Hons),PhD(MolBiology)isascientistconductingangiogenesisresearch.
Particularlyheisinterestedinmolecularfactorsmodulatingangiogenesisinvarioussettingssuchasstrokeandcancer.
HeisaPost-DoctoralFellowandco-supervisesseveralgraduatestudents.
Petcuetal.
JournalofAngiogenesisResearch2010,2:26http://www.
jangiogenesis.
com/content/2/1/26Page7of10RIM,MD,PhD(Neurorehabilitation)isanacademicphysicianwithspecialinterestsinresearchinNeuroanatomyandNeurorehabilitationafterstrokeincludingthepotentialroleofmodulatorsofangiogenesisinthispathologicalentity.
Sheistheheadofherdepartmentwhereshecurrentlyworks.
MMO,MD,PhD(Cardiology)isanacademicphysicianinterestedinangiogenesismodulationinseveralpathologicalentitiesincludingatheroscleroticischemicstrokeandcardiovasculardisease.
Sheisthesectionheadinheracademicinstitution.
CompetinginterestsInthepastfiveyears,theauthorsofthisarticlehavenotreceivedreimbursements,fees,funding,orsalaryfromanorganizationthatmayinanywaygainorlosefinanciallyfromthepublicationofthismanuscript,eithernoworinthefuture.
Theauthorsofthisarticledonotholdanystocksorsharesinanorganizationthatmayinanywaygainorlosefinanciallyfromthepublicationofthismanuscript,eithernoworinthefutureTheauthorsofthisarticledonotholdorarecurrentlyapplyingforanypatentsrelatingtothecontentofthemanuscript.
Theauthorsofthisarticlehavenotreceivedreimbursements,fees,funding,orsalaryfromanorganizationthatholdsorhasappliedforpatentsrelatingtothecontentofthemanuscript.
Theauthorsofthisarticlehavenootherfinancialcompetinginterests.
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