Retinal Vascular Disease PDF
Preview Retinal Vascular Disease
A.M.Joussen · T.W.Gardner · B.Kirchhof · S.J.Ryan(Eds.) RetinalVascularDisease A.M. Joussen · T.W. Gardner · B. Kirchhof · S.J. Ryan (Eds.) Retinal Vascular Disease With565Figuresin1043Partsand330Tables AntoniaM.Joussen,MD,PhD ProfessorofOphthalmology DepartmentofOphthalmology,UniversityofDüsseldorf Moorenstraße5,40225Düsseldorf,Germany ThomasW.Gardner,MD,MS ProfessorofOphthalmology DepartmentofOphthalmology PennStateCollegeofMedicine 500University DriveBox850 Hershey,PA17033,USA BerndKirchhof,MD ProfessorofOphthalmology DepartmentofVitreoretinalSurgery CenterforOphthalmology UniversityofCologne Joseph-Stelzmann-Straße9,50931Cologne,Germany StephenJ.Ryan,MD ProfessorofOphthalmology DohenyEyeInstitute,UniversityofSouthernCalifornia 1450SanPabloStreet,LosAngeles,CA90033,USA ISBN978-3-540-29541-9 Springer-VerlagBerlinHeidelbergNewYork LibraryofCongressControlNumber:2007931904 Thisworkissubjecttocopyright.Allrightsarereserved,whetherthewholeorpartofthe materialisconcerned,specificallytherightsoftranslation,reprinting,reuseofillustrations, recitation,broadcasting,reproductiononmicrofilmorinanyotherway,andstorageindata banks.Duplicationofthispublicationorpartsthereofispermittedonlyundertheprovisions oftheGermanCopyrightLawofSeptember9,1965,initscurrentversion,andpermissionfor usemustalwaysbeobtainedfromSpringer-Verlag.Violationsareliableforprosecutionunder theGermanCopyrightLaw. SpringerisapartofSpringerScience+BusinessMedia http://www.springer.com Springer-VerlagBerlinHeidelberg2007 PrintedinGermany Theuseofgeneraldescriptivenames,registerednames,trademarks,etc.inthispublication doesnotimply,evenintheabsenceofaspecificstatement,thatsuchnamesareexemptfrom therelevantprotectivelawsandregulationsandthereforefreeforgeneraluse. Productliability:Thepublisherscannotguaranteetheaccuracyofanyinformationaboutthe applicationofoperativetechniquesandmedicationscontainedinthisbook.Ineveryindividual casetheusermustchecksuchinformationbyconsultingtherelevantliterature. Editor:MarionPhilipp,Heidelberg,Germany DeskEditor:MartinaHimberger,Heidelberg,Germany ProductionEditor:JoachimW.Schmidt,München,Germany Coverdesign:eStudioCalamar,Spain Typesetting:FotoSatzPfeiferGmbH,D-82166Gräfelfing Printedonacid-freepaper–24/3150–543210 Foreword Angiogenesisinhibitorscompriseanewclassofdrugsthathaverecentlyreceived FDAapprovalforuseinage-relatedmaculardegeneration.Theyarecurrentlyin clinicaltrialsforthetreatmentofdiabeticretinopathy.Thesenewdrugsemerged aftermorethanthreedecadesofcancerresearch.Thisjourneywasdrivenbythe hypothesis that tumor growth is angiogenesis dependent, and sustained by experimental demonstrations that antiangiogenic therapy could become a fourthmodalitytohelpcontrolneoplasticdisease. Atthedawningofthisnewfieldofangiogenesisresearch,animalmodelsof corneal neovascularization became the test tube for discovery of angiogenesis regulatorymolecules.Itseemsmorethanacoincidencethatthetwoimplantable polymersstillemployedbyscientiststodayforslowreleaseofangiogenesisregu- latory molecules into the avascular cornea as a bioassay, originated from soft contactlensesorfromawearabledevicetotreatglaucoma.Inthissense,twodis- tinct specialties of medicine, oncology and ophthalmology, are now linked. Angiogenesishasbecometheorganizingprinciple. Overtheyears,numerousophthalmologistshavestudiedinacancerbiologylab andhavegoneontodistinguishedcareersinophthalmology.Withouttheircontri- butions it is unlikely that an oncologist’s armamentarium would today contain approvedanti-cancerdrugsthatinhibitangiogenesisdirectlyorindirectly. Itisasexcitingthatthesenewdrugshavebeguntoincreasesurvivalforthethree commoncancers,colon,breastandlung,asitisthateyesighthasbeenimprovedin patients with age-related macular degeneration (“A very effective treatment for neovascularmaculardegeneration,”E.M.Stone,NEnglJMed2006355:1493). Theeditorsandauthorsofthisbookhavebroughtthefieldofretinalvascular diseaseuptodate,astheprinciplesofantiangiogenictherapyarerapidlybeing translatedtoclinicalpractice.Thisbookisalsoveryvaluablebecauseitinspires thereader tothinkaboutpossible futureimprovements in the management of retinalvasculardiseases.Canbiomarkersinthebloodorurinebedevelopedto detectrecurrenceofretinalneovascularizationbeforesymptomsorbeforedetec- tionbyophthalmoscopy?Canoralangiogenesisinhibitorsmaintainsuppression ofneovascularmaculardegenerationaftersighthasbeenimprovedbyrepeated intravitrealinjectionsofantiangiogenicdrugs?Becauseplateletsarenowknown to carry high concentrations of angiogenesis regulatory molecules stored and segregatedinalphagranules,willitbecomepossibletotherapeuticallyinstruct plateletstoreleaseantiangiogenicproteins?Beyondthesequestionsitispossible toanticipatethatangiogenesisresearchwillcontinuetobringnewinsightsinto thebiologyandmolecularmechanismsofretinalvasculardisease. JudahFolkman,MD Preface Great progress has been made in the treatment of vascular disease in recent years,andwehopeandexpectthisisapreludetoevengreaterprogressinthe nearfuture.Theadventofclinicallyapplicableanti-VEGFtherapiesisonlythe “tipoftheiceberg”offutureadditionstotheclinicalarmamentarium.However, thereisnouniqueformulaforangiogenesis.Ourunderstandingofcomplexdis- easespecificinteractionsisdependentonaknowledgeofthebasicmechanisms involved in the vascular reactions specific to different disease entities. Despite thesenewtreatmentsandtheexplosionofknowledgeonthebasicmechanisms ofvascularbiology,vasculardiseaseoftheretinaremainstodateamajorcause ofblindnessinallagegroups. Thetopicscoveredbythisbookrangefromfundamentalconceptsofmolecu- larbiologytobasicclinicalappearance,specificpathologyandtreatmentofreti- nalvasculardisease. Inthefirstpart,thecurrentthinkinginvascularbiologyisdiscussedinrela- tiontoretinalvasculardisease.Theemphasisisongeneralpathogenicconcepts includingischemia,inflammationandtheirassociatedpathology.Experimental approachesarereviewedaswellasanimalmodelswhichmighthelpintheinves- tigationofthediseases. Thesecondpartincludesmoderndiagnosticfeaturesandgeneraltreatment strategies. Diagnostic procedures are discussed with respect to their relevance forclinicaldecisionmaking.Similarly,treatmentproceduresaredescribedstep- wisebyschematicgraphics. Thethirdpart describeseachdiseaseinacomprehensivemannerincluding demographics, clinical course and treatment. Clinical image series including illustratedsinglecasefollow-upsaregivenmajoremphasisandprovideanatlas likepresentation.Thebookincludestopicswhicharenotcurrentlyfoundinoth- er textbooks of retinal disease including case reports and clinical follow-ups. Furthermore, all the treatment procedures are explained in detail to facilitate theirusebyophthalmologistsintraining. Morethan50expertsinthefieldcontributedtothisstateoftheartreviewof basicandclinicalscience,whichaimstoenhanceourunderstandingofretinal vasculardiseaseandtohelptheclinicianintheevaluationofcurrentandfuture treatment approaches. The authors are internationally recognized leaders in clinicalophthalmology,includingtheareasofmedicalretina,vitreoretinalsur- gery,anduveitis.Inauniquewayleadersandexpertsintheirfieldsofmolecular mechanismsandgeneralconceptsofvascularsurgeryhavecontributedto this bookeventhoughtheirpreviousmajorfocushasnotnecessarilybeenonoph- thalmicdisease. Nevertheless, the field of vascular biology and retinal vascular disease is so broadandtheevolutionofknowledgesorapidthattheworkcannotbecompre- hensiveandtheinformationgivenonlyresemblesthecurrentknowledgeatthe timeofprinting. Asamultiauthoredtext,therearemanyliterarystyles,andtheeditorshave not sacrificed the originality and the style of the individual authors. Although VIII Preface there will be some aspects that are discussed in more than one chapter, the uniqueinterpretationbyeachauthorjustifiessomeoverlapandisanattractive feature. The editors gratefully acknowledge the support of the contributing authors who,inadditiontotheirlargeclinicalloadandscientificresearchefforts,found thetimetomakesuchalargecontributiontothecompletionofthisproject.In particular, Andrew P. Schachat, MD, and his team at The Wilmer Eye Institute wereofinvaluablehelp. At Springer, Marion Philipp and Martina Himberger helped to create this bookanditsuniquecombinationofbasicscienceandclinicalapplication. WehopethatRetinalVascularDiseasewillhelptoinspirecliniciansandscien- tistsinthefuturetomakingfurthereffortsandadvancesinthisfield. Düsseldorf,Hershey,Cologne,LosAngeles August2007 AntoniaM.Joussen ThomasW.Gardner BerndKirchhof StephenJ.Ryan IX Contents SectionI: PathogenesisofRetinalVascularDisease 1 FunctionalAnatomy,FineStructureandBasicPathology oftheRetinalVasculature D.B.Archer,T.A.Gardiner,A.W.Stitt ....................... 3 1.1 AnatomicalOrganizationoftheRetinalVasculature ............... 3 1.1.1 MicrovascularArrangement ................................... 3 1.1.2 NatureoftheRetinalVasculature............................... 6 1.2 ResponsesoftheRetinaandItsVasculaturetoStressandDisease: HistologicalandPathologicalConsequences ..................... 7 1.2.1 HemodynamicChanges....................................... 7 1.2.2 OxygenSaturationChanges ................................... 11 1.2.3 Occlusion–Ischemia ......................................... 12 1.2.4 RepairandRemodeling ....................................... 13 1.2.5 MetabolicStresses ........................................... 14 1.2.6 Trauma..................................................... 17 1.2.7 DrugToxicity ............................................... 18 1.2.8 Inflammation ............................................... 18 1.2.9 Retinal-ChoroidalTumors..................................... 20 1.2.10 PrimaryNeuropileAtrophyandDegeneration.................... 22 1.2.11 RemoteEffectsofRetinalVascularPathology .................... 22 References........................................................ 22 2 RetinalVascularDevelopment M.I.Dorrell,M.Friedlander,L.E.H.Smith .................. 24 2.1 Introduction ................................................ 24 2.1.1 GeneralVascularDevelopment................................. 24 2.1.2 BasisofClinicalIdentificationofBloodVessels ................... 24 2.1.3 MajorCellularComponentsofVesselFormation.................. 25 2.2 EndothelialCells............................................. 25 2.2.1 VascularHeterogeneity(MorphologicalClassificationofVessels).... 25 2.3 MuralCells ................................................. 25 2.4 VascularPatterning .......................................... 26 2.5 RetinalVascularDevelopment ................................. 27 2.5.1 TheRoleofAstrocytes........................................ 29 2.5.2 TheRoleofSubcellularEndothelialProcesses .................... 31 2.6 DevelopmentoftheDeepRetinalVascularPlexuses ............... 32 2.7 VascularMaturation.......................................... 32 2.8 VascularPruningMechanisms ................................. 34 2.9 MouseRetinalVascularDevelopmentasaModelforGeneral VascularDevelopment ........................................ 34 2.10 UseofRetinalVascularDevelopmentasModelsforClinicalOcular Neovascularization........................................... 35 X Contents 2.10.1 MouseRetinalAngiogenesisModel ............................ 35 2.10.2 Oxygen-InducedRetinopathy ................................. 35 References........................................................ 35 3 RetinalAngiogenesisandGrowthFactors 3.1 GeneralConceptsofAngiogenesisandVasculogenesis C.RuizdeAlmodovar,A.Ny,P.Carmeliet .................. 38 3.1.1 GeneralIntroduction ........................................ 38 3.1.2 AngiogenicDisorders........................................ 38 3.1.3 ModesofVesselGrowth...................................... 40 3.1.4 Vasculogenesis ............................................. 40 3.1.4.1 RoleofEndothelialProgenitorsintheEmbryo .................. 41 3.1.4.2 RoleofEndothelialProgenitorsintheAdult..................... 42 3.1.4.3 TheEndothelial/HematopoieticConnection–AnEmerging Theme .................................................... 44 3.1.4.4 Arterial,VenousandLymphaticCellFateSpecification ........... 44 3.1.4.5 Tissue-SpecificECDifferentiation ............................. 45 3.1.5 Angiogenesis ............................................... 46 3.1.5.1 VascularPermeabilityandExtracellularMatrixDegradation....... 46 3.1.5.2 EndothelialBuddingandSprouting............................ 48 3.1.5.3 VascularLumenFormation................................... 49 3.1.5.4 GuidedNavigationofVessels ................................. 50 3.1.5.5 VesselMaintenance ......................................... 51 3.1.6 Arteriogenesis.............................................. 52 3.1.6.1 SmoothMuscleProgenitorCells............................... 52 3.1.6.2 SmoothMuscleCellRecruitment,GrowthandDifferentiation ..... 53 3.1.7 TherapeuticImplications..................................... 54 References........................................................ 56 3.2 VascularEndothelialGrowthFactorinRetinalVascularDisease G.L.King,K.Suzuma,J.K.Sun ............................... 66 3.2.1 VEGFRegulationandReceptors............................... 66 3.2.1.1 VEGFR2,PKC,PI3-kinase .................................... 66 3.2.2 VascularEndothelialGrowthFactor ........................... 67 3.2.3 VEGFandSystemicDiseases.................................. 68 3.2.4 VEGFandRetinalVascularDisease ............................ 68 3.2.4.1 VEGFandOtherGrowthFactors .............................. 68 3.2.4.2 VEGFandDiabeticRetinopathy............................... 69 3.2.4.3 HypertensionAsanAggravatingFactorinDiabetes-Induced ActivationofVEGF.......................................... 70 3.2.4.4 VEGFinNeovascularizationSecondarytoRetinalVascular Occlusions ................................................. 70 References........................................................ 70 3.3 InvolvementoftheEphrin/EphSysteminAngioproliferative OcularDiseases H.Agostini,G.Martin..................................... 73 3.3.1 FirstStudies:EphrinsinRetinotectalProjection ................. 73 3.3.2 EphrinsinVascularDevelopment ............................. 74 3.3.3 EphrinsandOcularAngiogenesis ............................. 75 3.3.4 EphrinsinRetinalandSubretinalAnimalModels ................ 75 3.3.5 TherapeuticPotential........................................ 76 References........................................................ 76 Contents XI 4 HematopoieticStemCellsinVascularDevelopment andOcularNeovascularization N.Sengupta,M.B.Grant,S.Caballero,M.E.Boulton.......... 78 4.1 Background ................................................. 78 4.2 DevelopmentalOriginsofHSCs ................................ 78 4.2.1 HSCsLackRegionalPatterning ................................. 79 4.3 DefiningtheAdultHSC ....................................... 79 4.3.1 HSCSelf-Renewal ............................................ 79 4.3.2 HSCPluripotency/Plasticity.................................... 81 4.4 TheHSCNiche............................................... 82 4.4.1 MolecularMechanismsforMaintenanceintheNiche .............. 82 4.5 HSCMobilization ............................................ 82 4.5.1 TheSDF-1/CXCR4Axis........................................ 84 4.6 SurfaceMarkerExpression–HSCIdentification .................. 84 4.7 SurfaceMarkerExpression–HSCIsolation....................... 84 4.8 Methodologies ............................................... 85 4.8.1 ExtractionofHSCfromDonorMice ............................ 85 4.8.2 ReconstitutionofBoneMarrow-AblatedRecipientMice ............ 85 4.8.3 EPCCulture ................................................. 86 4.9 MouseModelsofHSCInvolvementinOcularNeovascularization .... 88 4.9.1 PreretinalNeovascularization .................................. 88 4.9.2 IrisNeovascularization........................................ 89 4.9.3 ChoroidalNeovascularization .................................. 90 4.10 Conclusion .................................................. 90 References........................................................ 91 5 InflammationasaStimulusforVascularLeakage andProliferation A.M.Joussen,A.P.Adamis .................................... 97 5.1 EvidenceforInflammationinthePathogenesisofDiabeticRetinopathy 97 5.1.1 UpregulationofInflammatoryMediatorsinDiabeticRetinopathy ..... 97 5.1.2 DiabeticRetinalPathologyCanBeInhibitedbyAnti-inflammatory Agents ...................................................... 98 5.1.3 VEGFIsaKeyMediatorofInflammatoryChangesintheDiabetic Retina:GeneralConsiderations ................................. 99 5.1.4 Angiopoietin-1RegulatesVascularPermeabilityandExpressionof InflammatoryMediatorsinDiabeticRetinopathy.................. 99 5.2 CellularandMolecularMechanismsMediatingDiabetes-Associated VascularDamageandtheNeovascularizingResponsetoIschemia .... 101 5.2.1 LeukocytesMediateRetinalVascularRemodelingDuringDevelop- mentandVaso-obliterationinDisease .......................... 101 5.2.2 VEGFandLeukocyteInvasionAreImportantFactorsinRegulating BothIschemia-MediatedOcularNeovascularizationandVascular DamageinDiabeticRetinopathy............................... 102 5.2.3 RegulationofIschemia-MediatedRetinalVascularization.......... 102 5.2.4 DiabetesAssociatedVascularDamageIsAcceleratedbyLeukostasis andFas-FasL-MediatedApoptosis.............................. 103 5.3 Conclusions ................................................ 103 References....................................................... 104 6 TheNeuronalInfluenceonRetinalVascularPathology A.J.Barber,H.D.VanGuilder,M.J.Gastinger ................ 108 6.1 Introduction................................................ 108 6.2 ThePhenotypeoftheRetinalVasculatureIsDeterminedbythe TissueItServes ............................................. 109 XII Contents 6.3 DiabetesCausesaLossoftheBlood-RetinalBarrierPhenotype ... 109 6.4 TheIncreaseinVascularPermeabilityIsLikelyDuetoanIncrease intheExpressionofVEGF ................................... 109 6.5 VEGFOriginatesfromtheNeuralTissueoftheRetina inDiabetes ................................................ 110 6.6 InjuryandNeurodegenerationintheBrainAreAccompaniedby IncreasedVEGFExpressionandVascularAbnormalities ......... 110 6.7 DiabetesIncreasesNeuralApoptosis,LeadingtoaCumulative ReductionintheThicknessoftheInnerLayersoftheRetina...... 111 6.8 SpecificNeuronsAreLostbyApoptosisinDiabetes ............. 113 6.9 NeuronsintheRetinaHaveMorphologicalCharacteristicsof Neurodegeneration ......................................... 113 6.10 TheGlialCellsoftheRetinaReacttoDiabetesAsifanInjury HasOccurred.............................................. 114 6.11 ThereisaLossofFunctioninDiabeticRetinopathythatBegins soonAftertheOnsetofDiabetes.............................. 115 6.12 Conclusions ............................................... 115 6.13 Methodology .............................................. 115 References....................................................... 116 7 HypoxiainthePathogenesisofRetinalDisease V.Poulaki................................................ 121 7.1 Introduction .............................................. 121 7.2 TheHIFPathwayandItsRoleinHypoxiaSignaling.............. 121 7.2.1 StructureoftheHIFTranscriptionFactorComplexandRegulation ofItsActivity .............................................. 122 7.2.2 DownstreamTargetsofHIF.................................. 123 7.2.3 ActivationofHIFbyNon-hypoxicStimuli...................... 124 7.2.4 VHLandItsRoleinRetinalAngiogenesis ...................... 124 7.3 VEGF .................................................... 125 7.4 RetinalHypoxiaandRetinopathyofPrematurity................ 126 7.4.1 Introduction .............................................. 126 7.4.2 PathophysiologyofRetinopathyofPrematurity ................. 126 7.5 RetinalHypoxiaandDiabeticRetinopathy ..................... 129 7.5.1 Introduction .............................................. 129 7.5.2 PathophysiologyofDiabeticRetinopathy ...................... 129 7.6 RetinalHypoxiaandVascularOcclusiveDisease ................ 131 7.7 OtherDiseases............................................. 132 7.7.1 CystoidMacularEdema ..................................... 132 7.7.2 RetinalDegeneration ....................................... 132 7.7.3 Glaucoma ................................................. 133 7.7.4 RetinalDetachment ........................................ 134 7.8 Conclusions ............................................... 134 References....................................................... 134 8 BloodRetinalBarrier 8.1 Blood-RetinalBarrier,RetinalVascularLeakage andMacularEdema B.E.Phillips,D.A.Antonetti .............................. 139 8.1.1 Introduction .............................................. 139 8.1.2 CharacteristicsoftheBlood-RetinalBarrier .................... 139 8.1.2.1 Blood-RetinalBarrierPhysiology ............................. 139 8.1.2.2 Fenestrations .............................................. 140 8.1.2.3 EndocytosisandFacilitatedDiffusion ......................... 140 8.1.2.4 WaterTransport ........................................... 140
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