Table Of ContentA.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
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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
