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.
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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.
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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.
Received:24August2010Accepted:26November2010Published:26November2010References1.
PetcuEB,SfredelV,PlattD,HerndonJG,KesslerC:Popa-WagnerACellularandmoleculareventsunderlyingthedysregulatedresponseoftheagedbraintostroke:amini-review.
Gerontology2008,54(1):6-17.
2.
PetcuEB,KocherT,KuhrA,BugaAM,KltingI,HerndonJG,KesslerC,Popa-WagnerA:Mildsystemicinflammationhasaneuroprotectiveeffectafterstrokeinrats.
CurrNeurovascRes2008,5(4):214-23.
3.
Popa-WagnerA,PiriciD,PetcuEB,MogoantaL,BugaAM,RosenCL,LeonR,HuberJ:Pathophysiologyofthevascularwallanditsrelevanceforcerebrovasculardisordersinagedrodents.
CurrNeurovascRes2010,7(3):251-67.
4.
GrahamSH,ChenJ:Programmedcelldeathincerebralischemia.
JCerebBloodFlowMetab2001,21(2):99-109.
5.
FlammeI,FrlichT,RisauW:Molecularmechanismsofvasculogenesisandembryonicangiogenesis.
JCellPhysiol1997,173(2):206-10.
6.
MartiHJ,BernaudinM,BellailA,SchochH,EulerM,PetitE,RisauW:Hypoxia-inducedvascularendothelialgrowthfactorexpressionprecedesneovascularizationaftercerebralischemia.
AmJPathol2000,156(3):965-76.
7.
YamashitaT,NinomiyaM,HernándezAcostaP,García-VerdugoJM,SunaboriT,SakaguchiM,AdachiK,KojimaT,HirotaY,KawaseT,ArakiN,AbeK,OkanoH,SawamotoK:Subventricularzone-derivedneuroblastsmigrateanddifferentiateintomatureneuronsinthepost-strokeadultstriatum.
JNeurosci2006,26(24):6627-36.
8.
KokaiaZ,ThoredP,ArvidssonA,LindvallO:Regulationofstroke-inducedneurogenesisinadultbrain–recentscientificprogress.
CerebCortex2006,16(Suppl1):i162-7.
9.
ThoredP,WoodJ,ArvidssonA,CammengaJ,KokaiaZ,LindvallO:Long-termneuroblastmigrationalongbloodvesselsinanareawithtransientangiogenesisandincreasedvascularizationafterstroke.
Stroke2007,38(11):3032-9.
10.
PlateKH,BeckH,DannerS,AllegriniPR,WiessnerC:CelltypespecificupregulationofvascularendothelialgrowthfactorinanMCA-occlusionmodelofcerebralinfarct.
JNeuropatholExpNeurol1999,58(6):654-66.
11.
SlevinM,KrupinskiJ,RoviraN,TuruM,LuqueA,BaldellouM,SanfeliuC,deVeraN,BadimonL:Identificationofpro-angiogenicmarkersinbloodvesselsfromstroked-affectedbraintissueusinglaser-capturemicrodissection.
BMCGenomics2009,10:113.
12.
BrodyH:Organizationofthecerebralcortex.
III.
Astudyofaginginthehumancerebralcortex.
JCompNeurol1955,102(2):511-6.
13.
JerniganTL,ArchibaldSL,Fennema-NotestineC,GamstAC,StoutJC,BonnerJ,HesselinkJR:Effectsofageontissuesandregionsofthecerebrumandcerebellum.
NeurobiolAging2001,22(4):581-94.
14.
MiyahiraY,YuJ,HiramatsuK,ShimazakiY,TakedaY:BrainvolumetricMRIstudyinhealthyelderlypersonsusingstatisticalparametricmapping.
SeishinShinkeigakuZasshi2004,106(2):138-51.
15.
CuriatiPK,TamashiroJH,SquarzoniP,DuranFL,SantosLC,WajngartenM,LeiteCC,ValladaH,MenezesPR,ScazufcaM,BusattoGF,AlvesTC:BrainstructuralvariabilityduetoagingandgenderincognitivelyhealthyElders:resultsfromtheSaoPauloAgeingandHealthstudy.
AmJNeuroradiol2009,30(10):1850-6.
16.
PakkenbergB,GundersenHJ,MortensenEL,LauritzenMJ,JeuneB,RegeurL,WestMJ,SchwartzTW:Thenormalbrain:anewknowledgeindifferentfields.
UgeskrLaeger1997,159(6):723-7.
17.
MerrillDA,RobertsJA,TuszynskiMH:ConservationofneuronnumberandsizeinentorhinalcortexlayersII,III,andV/VIofagedprimates.
JCompNeurol2000,422(3):396-401.
18.
WalterJ,KeinerS,WitteOW,RedeckerC:Differentialstroke-inducedproliferativeresponseofdistinctprecursorcellsubpopulationsintheyoungandageddentategyrusNeuroscience.
2010,169(3):1279-86.
19.
KnoxCA,OliveiraA:BrainaginginnormotensiveandhypertensivestrainsofratsIII.
Aquantitativestudyofcerebrovasculature.
ActaNeuropathol1980,52(1):17-25.
20.
Meier-RugeW,HunzikerO,SchulzU,ToblerHJ,SchweizerA:Stereologicalchangesinthecapillarynetworkandnervecellsoftheaginghumanbrain.
MechAgeingDev1980,14(1-2):233-43.
21.
SonntagWE,LynchCD,CooneyPT,HutchinsPM:Decreasesincerebralmicrovasculaturewithageareassociatedwiththedeclineingrowthhormoneandinsulin-likegrowthfactor1.
Endocrinology1997,138(8):3515-20.
22.
HughesCC,LantosPL:Amorphometricstudyofbloodvessel,neuronandglialcelldistributioninyoungandoldratbrain.
JNeurolSci1987,79(1-2):101-10.
23.
AmentaF,FerranteF,ManciniM,SabbatiniM,VegaJA,ZaccheoD:Effectoflong-termtreatmentwiththedihydropyridine-typecalciumchannelblockerdarodipine(PY108-068)onthecerebralcapillarynetworkinagedrats.
MechAgeingDev1995,78(1):27-37.
24.
IngrahamJP,ForbesME,RiddleDR,SonntagWE:Agingreduceshypoxia-inducedmicrovasculargrowthintherodenthippocampus.
JGerontolABiolSciMedSci2008,63(1):12-20.
25.
FarkasE,deVosRA,DonkaG,JansenSteurEN,MihályA,LuitenPG:Age-relatedmicrovasculardegenerationinthehumancerebralperiventricularwhitematter.
ActaNeuropathol2006,111(2):150-7,Epub2006Feb2.
26.
HajduMA,HeistadDD,SiemsJE,BaumbachGL:Effectsofagingonmechanicsandcompositionofcerebralarteriolesinrats.
CircRes1990,66(6):1747-54.
27.
deJongGI,TraberJ,LuitenPG:Formationofcerebrovascularanomaliesintheageingratisdelayedbychronicnimodipineapplication.
MechAgeingDev1992,64(3):255-72.
28.
KeukerJI,LuitenPG,FuchsE:CapillarychangesinhippocampalCA1andCA3areasoftheagingrhesusmonkey.
ActaNeuropathol2000,100(6):665-72.
29.
FarkasE,LuitenPG:CerebralmicrovascularpathologyinagingandAlzheimer'sdisease.
ProgNeurobiol2001,64(6):575-611.
30.
ShahGN,MooradianAD:Age-relatedchangesintheblood-brainbarrier.
ExpGerontol1997,32(4-5):501-19.
31.
FarkasE,DeJongGI,ApróE,KeukerJI,LuitenPG:Calciumantagonistsdecreasecapillarywalldamageinaginghypertensiveratbrain.
NeurobiolAging2001,22(2):299-309.
32.
ZhangY,PengYY,ChenGY,ChenWF:Cerebralbloodflow,cerebralbloodvolume,oxygenutilizationandoxygenextractionfraction:theinfluenceofage.
NanFangYiKeDaXueXueBao2010,30(6):1237-9.
33.
GjeddeA,DiemerNH:Double-tracerstudyofthefineregionalblood-brainglucosetransferintheratbycomputer-assistedautoradiography.
JCerebBloodFlowMetab1985,5(2):282-9.
34.
OmarNM,MarshallJM:Age-relatedchangesinsympatheticinnervationofcerebralvesselsandincarotidvascularresponsestonorepinephrine:invitroandinvivostudies.
JApplPhysiol2010,109(2):314-22.
35.
GoldmanH,BermanRF,GershonS,MurphySL,AltmanHJ:Correlationofbehavioralandcerebrovascularfunctionsintheagingrat.
NeurobiolAging1987,8(5):409-16.
Petcuetal.
JournalofAngiogenesisResearch2010,2:26http://www.
jangiogenesis.
com/content/2/1/26Page8of1036.
GoldmanH,BermanRF,GershonS,MurphyS,MoreheadM,AltmanHJ:Cerebrovascularpermeabilityandcognitionintheagingrat.
NeurobiolAging1992,13(1):57-62.
37.
BermanRF,GoldmanH,AltmanHJ:Age-relatedchangesinregionalcerebralbloodflowandbehaviorinSprague-Dawleyrats.
NeurobiolAging1988,9(5-6):691-6.
38.
GrinbergLT,ThalDR:Vascularpathologyintheagedhumanbrain.
ActaNeuropathol2010,119(3):277-290.
39.
IsaacsKR,AndersonBJ,AlcantaraAA,BlackJE,GreenoughWT:Exerciseandthebrain:angiogenesisintheadultratcerebellumaftervigorousphysicalactivityandmotorskilllearning.
JCerebBloodFlowMetab1992,12(1):110-9,Erratumin:JCerebBloodFlowMetab1992May;12(3):533.
40.
CarmelietP:Angiogenesisinlife,diseaseandmedicine.
Nature2005,438(7070):932-6.
41.
YamashitaT,NinomiyaM,HernándezAcostaP,García-VerdugoJM,SunaboriT,SakaguchiM,AdachiK,KojimaT,HirotaY,KawaseT,ArakiN,AbeK,OkanoH,SawamotoK:Subventricularzone-derivedneuroblastsmigrateanddifferentiateintomatureneuronsinthepost-strokeadultstriatum.
JNeurosci2006,26(24):6627-36.
42.
SlevinM,KrupinskiJ,BadimonL:Controllingtheangiogenicswitchindevelopingatheroscleroticplaques:possibletargetsfortherapeuticintervention.
JAngiogenesRes2009,1:4.
43.
LeiZN,ZhangLM,SunFY:Beta-cateninsiRNAinhibitsischemia-inducedstriatalneurogenesisinadultratbrainfollowingatransientmiddlecerebralarteryocclusion.
NeurosciLett2008,435(2):108-12.
44.
ConductierG,BlondeauN,GuyonA,NahonJL,RovèreC:TheroleofmonocytechemoattractantproteinMCP1/CCL2inneuroinflammatorydiseases.
JNeuroimmunol2010,224(1-2):93-100.
45.
Sakurai-YamashitaY,ShigematsuK,YamashitaK,NiwaM:ExpressionofMCP-1inthehippocampusofSHRSPwithischemia-relateddelayedneuronaldeath.
CellMolNeurobiol2006,26(4-6):823-31.
46.
QiuJ,XuJ,ZhengY,WeiY,ZhuX,LoEH,MoskowitzMA,SimsJR:High-MobilityGroupBox1PromotesMetalloproteinase-9upregulationThroughToll-LikeReceptor4AfterCerebralIschemia.
Stroke2010,41(9):2077-82.
47.
KurzepaJ,BielewiczJ,GrabarskaA,StelmasiakZ,Stryjecka-ZimmerM,Bartosik-PsujekH:Matrixmetalloproteinase-9contributestotheincreaseoftauproteininserumduringacuteischemicstroke.
JClinNeurosci2010,17(8):997-9.
48.
DongX,SongYN,LiuWG,GuoXL:CurrNeuropharmacol2009,7(4):269-75.
49.
SuzukiY:Mmp-9,apotentialtargetforcerebralischemictreatment.
Roleoftissue-typeplasminogenactivatorinischemicstroke.
JPharmacolSci2010,113(3):203-7.
50.
JinR,YangG,LiG:Molecularinsightsandtherapeutictargetsforblood-brainbarrierdisruptioninischemicstroke:criticalroleofmatrixmetalloproteinasesandtissue-typeplasminogenactivator.
NeurobiolDis2010,38(3):376-85.
51.
BckM,KetelhuthDF,AgewallS:Matrixmetalloproteinasesinatherothrombosis.
ProgCardiovascDis2010,52(5):410-28.
52.
RosenbergGA:Matrixmetalloproteinasesinneuroinflammation.
Glia2002,39(3):279-91.
53.
WangG,GuoQ,HossainM,FazioV,ZeynalovE,JanigroD,MaybergMR,NamuraS:Bonemarrow-derivedcellsarethemajorsourceofMMP-9contributingtoblood-brainbarrierdysfunctionandinfarctformationafterischemicstrokeinmice.
BrainRes2009,1294:183-92.
54.
KangSS,KookJH,HwangS,ParkSH,NamSC,KimJK:Inhibitionofmatrixmetalloproteinase-9attenuatedneuralprogenitorcellmigrationafterphotothromboticischemia.
BrainRes2008,1228:20-6.
55.
FatarM,StroickM,SteffensM,SennE,ReuterB,BukowS,GriebeM,AlonsoA,LichtnerP,BugertP,MeitingerT,WienkerTF,HennericiMG:Single-nucleotidepolymorphismsofMMP-2geneinstrokesubtypes.
CerebrovascDis2008,26(2):113-9.
56.
LiuR,LiuQ,HeS,SimpkinsJW,YangSH:Combinationtherapyof17beta-estradiolandrecombinanttissueplasminogenactivatorforexperimentalischemicstroke.
JPharmacolExpTher2010,332(3):1006-12.
57.
MachadoLS,SazonovaIY,KozakA,WileyDC,El-RemessyAB,ErgulA,HessDC,WallerJL,FaganSC:Minocyclineandtissue-typeplasminogenactivatorforstroke:assessmentofinteractionpotential.
Stroke2009,40(9):3028-33.
58.
HorstmannS,KoziolJA,Martinez-TorresF,NagelS,GardnerH,WagnerS,Sonographicmonitoringofmasseffectinstrokepatientstreatedwithhypothermia:Correlationwithintracranialpressureandmatrixmetalloproteinase2and9expression.
JNeurolSci2009,276(1-2):75-8.
59.
BakerAH,SicaV,WorkLM,Williams-IgnarroS,deNigrisF,LermanLO,CasamassimiA,LanzaA,SchianoC,RienzoM,IgnarroLJ,NapoliCL:Brainprotectionusingautologousbonemarrowcell,metalloproteinaseinhibitors,andmetabolictreatmentincerebralischemia.
ProcNatlAcadSciUSA2007,104(9):3597-602.
60.
RajpathakSN,WangT,Wassertheil-SmollerS,StricklerHD,KaplanRC,McGinnAP,WildmanRP,RosenbaumD,RohanTE,SchererPE,CushmanM,HoGY:Hepatocytegrowthfactorandtheriskofischemicstrokedevelopingamongpostmenopausalwomen:resultsfromtheWomen'sHealthInitiative.
Stroke2010,41(5):857-62.
61.
NagayamaT,NagayamaM,KoharaS,KamiguchiH,ShibuyaM,KatohY,ItohJ,ShinoharaY:Post-ischemicdelayedexpressionofhepatocytegrowthfactorandc-Metinmousebrainfollowingfocalcerebralischemia.
BrainRes2004,999(2):155-66.
62.
CuiX,ChenJ,ZacharekA,RobertsC,YangY,ChoppM:Nitricoxidedonorup-regulationofSDF1/CXCR4andAng1/Tie2promotesneuroblastcellmigrationafterstroke.
JNeurosciRes2009,87(1):86-95.
63.
ChenJ,CuiX,ZacharekA,ChoppM:IncreasingAng1/Tie2expressionbysimvastatintreatmentinducesvascularstabilizationandneuroblastmigrationafterstroke.
JCellMolMed2009,13(7):1348-57.
64.
ZacharekA,ChenJ,CuiX,LiA,LiY,RobertsC,FengY,GaoQ,ChoppM:Angiopoietin1/Tie2andVEGF/Flk1inducedbyMSCtreatmentamplifiesangiogenesisandvascularstabilizationafterstroke.
JCerebBloodFlowMetab2007,27(10):1684-91.
65.
RosensteinJM,KrumJM:NewrolesforVEGFinnervoustissue–beyondbloodvessels.
ExpNeurol2004,187(2):246-53.
66.
BrownWR:Areviewofstringvesselsorcollapsed,emptybasementmembranetubes.
JAlzheimersDis2010,21(3):725-39.
67.
PalmerTD,WillhoiteAR,GageFH:Vascularnicheforadulthippocampalneurogenesis.
JCompNeurol2000,425(4):479-94.
68.
SunY,JinK,XieL,ChildsJ,MaoXO,LogvinovaA,GreenbergDA:VEGF-inducedneuroprotection,neurogenesis,andangiogenesisafterfocalcerebralischemia.
JClinInvest2003,111(12):1843-51.
69.
JinK,ZhuY,SunY,MaoXO,XieL,GreenbergDA:Vascularendothelialgrowthfactor(VEGF)stimulatesneurogenesisinvitroandinvivo.
ProcNatlAcadSciUSA2002,99(18):11946-50,Epub2002Aug14.
70.
PlateKH,BeckH,DannerS,AllegriniPR,WiessnerC:CelltypespecificupregulationofvascularendothelialgrowthfactorinanMCA-occlusionmodelofcerebralinfarct.
JNeuropatholExpNeurol1999,58(6):654-66.
71.
MesriM,Morales-RuizM,AckermannEJ,BennettCF,PoberJS,SessaWC,AltieriDC:Suppressionofvascularendothelialgrowthfactor-mediatedendothelialcellprotectionbysurvivintargeting.
AmJPathol2001,158(5):1757-65.
72.
IssaR,KrupinskiJ,BujnyT,KumarS,KaluzaJ,KumarP:Vascularendothelialgrowthfactoranditsreceptor,KDR,inhumanbraintissueafterischemicstroke.
LabInvest1999,79(4):417-25.
73.
SlevinM,KrupinskiJ,SlowikA,KumarP,SzczudlikA,GaffneyJ:Serialmeasurementofvascularendothelialgrowthfactorandtransforminggrowthfactor-beta1inserumofpatientswithacuteischemicstroke.
Stroke2000,31(8):1863-70.
74.
TuruMM,SlevinM,MatouS,WestD,RodríguezC,LuqueA,Grau-OlivaresM,BadimonL,Martinez-GonzalezJ,KrupinskiJ:C-reactiveproteinexertsangiogeniceffectsonvascularendothelialcellsandmodulatesassociatedsignallingpathwaysandgeneexpression.
BMCCellBiol2008,9:47.
75.
BelloG,CailottoF,HanriotD,Kolopp-SardaMN,Latger-CannardV,HessK,ZannadF,LongroisD:RoparsC-reactiveprotein(CRP)increasesVEGF-AexpressioninmonocyticcellsviaaPI3-kinaseandERK1/2signalingdependentpathway.
Atherosclerosis2008,200(2):286-93.
76.
ShweikiD,ItinA,SofferD,KeshetE:Vascularendothelialgrowthfactorinducedbyhypoxiamaymediatehypoxia-initiatedangiogenesis.
Nature1992,359(6398):843-5.
77.
LaMannaJC,KuoNT,LustWD:Hypoxia-inducedbrainangiogenesis.
Signalsandconsequences.
AdvExpMedBiol1998,454:287-93.
78.
MartiHJ,BernaudinM,BellailA,SchochH,EulerM,PetitE,RisauW:Hypoxia-inducedvascularendothelialgrowthfactorexpressionprecedesneovascularizationaftercerebralischemia.
AmJPathol2000,156(3):965-76.
Petcuetal.
JournalofAngiogenesisResearch2010,2:26http://www.
jangiogenesis.
com/content/2/1/26Page9of1079.
HoehnBD,HarikSI,HudetzAG:VEGFmRNAexpressedinmicrovesselsofneonatalandadultratcerebralcortex.
BrainResMolBrainRes2002,101(1-2):103-8.
80.
EmerichDF,SchneiderP,BintzB,HudakJ,ThanosCG:Agingreducestheneuroprotectivecapacity,VEGFsecretion,andmetabolicactivityofratchoroidplexusepithelialcells.
CellTransplant2007,16(7):697-705.
81.
GaoP,ShenF,GabrielRA,LawD,YangE,YangGY,YoungWL,SuH:Attenuationofbrainresponsetovascularendothelialgrowthfactor-mediatedangiogenesisandneurogenesisinagedmice.
Stroke2009,40(11):3596-600.
82.
BeckH,AckerT,PüschelAW,FujisawaH,CarmelietP,PlateKH:Celltype-specificexpressionofneuropilinsinanMCA-occlusionmodelinmicesuggestsapotentialroleinpost-ischemicbrainremodeling.
JNeuropatholExpNeurol2002,61(4):339-50.
83.
FuhG,GarciaKC,deVosAM:Theinteractionofneuropilin-1withvascularendothelialgrowthfactoranditsreceptorflt-1.
JBiolChem2000,275(35):26690-5.
84.
Gluzman-PoltorakZ,CohenT,ShibuyaM,NeufeldG:Vascularendothelialgrowthfactorreceptor-1andneuropilin-2formcomplexes.
JBiolChem2001,276(22):18688-94.
85.
PungliaRS,LuM,HsuJ,KurokiM,TolentinoMJ,KeoughK,LevyAP,LevyNS,GoldbergMA,D'AmatoRJ,AdamisAP:Regulationofvascularendothelialgrowthfactorexpressionbyinsulin-likegrowthfactorI.
Diabetes1997,46(10):1619-26.
86.
AndersonMF,AbergMA,NilssonM,ErikssonPS:Insulin-likegrowthfactor-Iandneurogenesisintheadultmammalianbrain.
BrainResDevBrainRes2002,134(1-2):115-22.
87.
LichtenwalnerRJ,ForbesME,BennettSA,LynchCD,SonntagWE,RiddleDR:Intracerebroventricularinfusionofinsulin-likegrowthfactor-Iamelioratestheage-relateddeclineinhippocampalneurogenesis.
Neuroscience2001,107(4):603-13.
88.
SonntagWE,LynchCD,BennettSA,KhanAS,ThorntonPL,CooneyPT,IngramRL,McShaneT,Brunso-BechtoldJK:Alterationsininsulin-likegrowthfactor-1geneandproteinexpressionandtype1insulin-likegrowthfactorreceptorsinthebrainsofageingrats.
Neuroscience1999,88(1):269-79.
89.
ShettyAK,HattiangadyB,ShettyGA:Stem/progenitorcellproliferationfactorsFGF-2,IGF-1,andVEGFexhibitearlydeclineduringthecourseofaginginthehippocampus:roleofastrocytes.
Glia2005,51(3):173-86.
90.
Lopez-LopezC,LeRoithD,Torres-AlemanI:Insulin-likegrowthfactorIisrequiredforvesselremodellingintheadultbrain.
ProcNatlAcadSciUSA2004,101(26):9833-8,Epub2004Jun21.
91.
SchwabS,SprangerM,KrempienS,HackeW,BettendorfM:Plasmainsulin-likegrowthfactorIandIGFbindingprotein3levelsinpatientswithacutecerebralischemicinjury.
Stroke1997,28(9):1744-8.
92.
DentiL,AnnoniV,CattadoriE,SalvagniniMA,VisioliS,MerliMF,CorradiF,CeresiniG,ValentiG,HoffmanAR,CedaGP:Insulin-likegrowthfactor1asapredictorofischemicstrokeoutcomeintheelderly.
AmJMed2004,117(5):312-7.
93.
BeilharzEJ,RussoVC,ButlerG,BakerNL,ConnorB,SirimanneES,DragunowM,WertherGA,GluckmanPD,WilliamsCE,ScheepensA:Co-ordinatedandcellularspecificinductionofthecomponentsoftheIGF/IGFBPaxisintheratbrainfollowinghypoxic-ischemicinjury.
BrainResMolBrainRes1998,59(2):119-34.
94.
EndresM,PirizJ,GertzK,HarmsC,MeiselA,KronenbergG,Torres-AlemanI:Seruminsulin-likegrowthfactorIandischemicbraininjury.
BrainRes2007,1185:328-35,Epub2007Oct24.
95.
SchbitzWR,HoffmannTT,HeilandS,KollmarR,BardutzkyJ,SommerC,SchwabS:Delayedneuroprotectiveeffectofinsulin-likegrowthfactor-iafterexperimentaltransientfocalcerebralischemiamonitoredwithmri.
Stroke2001,32(5):1226-33.
96.
GuanJ,BennetL,GluckmanPD,GunnAJ:Insulin-likegrowthfactor-1andpost-ischemicbraininjury.
ProgNeurobiol2003,70(6):443.
97.
GuanJ,BennetL,GeorgeS,WuD,WaldvogelHJ,GluckmanPD,FaullRL,CrosierPS,GunnAJ:Insulin-likegrowthfactor-1reducespostischemicwhitematterinjuryinfetalsheep.
JCerebBloodFlowMetab2001,21(5):493-502.
98.
IssaR,AlQteishatA,MitsiosN,SakaM,KrupinskiJ,TarkowskiE,GaffneyJ,SlevinM,KumarS,KumarP:ExpressionofbasicfibroblastgrowthfactormRNAandproteininthehumanbrainfollowingischaemicstroke.
Angiogenesis2005,8(1):53-62.
99.
JumpSS,ChildsTE,ZwetslootKA,BoothFW,LeesSJ:Fibroblastgrowthfactor2-stimulatedproliferationislowerinmuscleprecursorcellsfromoldrats.
ExpPhysiol2009,94(6):739-48.
100.
VavkenP,SaadFA,MurrayMM:AgedependenceofexpressionofgrowthfactorreceptorsinporcineACLfibroblasts.
JOrthopRes2010,28(8):1107-12.
101.
BoisenL,DrasbekKR,PedersenAS,KristensenP:Evaluationofendothelialcellcultureasamodelsystemofvascularageing.
ExpGerontol2010,45(10):779-87.
doi:10.
1186/2040-2384-2-26Citethisarticleas:Petcuetal.
:Angiogenesisinold-agedsubjectsafterischemicstroke:acautionarynoteforinvestigators.
JournalofAngiogenesisResearch20102:26.
SubmityournextmanuscripttoBioMedCentralandtakefulladvantageof:ConvenientonlinesubmissionThoroughpeerreviewNospaceconstraintsorcolorgurechargesImmediatepublicationonacceptanceInclusioninPubMed,CAS,ScopusandGoogleScholarResearchwhichisfreelyavailableforredistributionSubmityourmanuscriptatwww.
biomedcentral.
com/submitPetcuetal.
JournalofAngiogenesisResearch2010,2:26http://www.
jangiogenesis.
com/content/2/1/26Page10of10
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