2024
Monoclonal antibodies that block Roundabout 1 and 2 signaling target pathological ocular neovascularization through myeloid cells
Geraldo L, Xu Y, Mouthon G, Furtado J, Leser F, Blazer L, Adams J, Zhang S, Zheng L, Song E, Robinson M, Thomas J, Sidhu S, Eichmann A. Monoclonal antibodies that block Roundabout 1 and 2 signaling target pathological ocular neovascularization through myeloid cells. Science Translational Medicine 2024, 16: eadn8388. PMID: 39565875, DOI: 10.1126/scitranslmed.adn8388.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodies, MonoclonalCorneal NeovascularizationDisease Models, AnimalHumansIntercellular Signaling Peptides and ProteinsMiceMice, Inbred C57BLMyeloid CellsNeovascularization, PathologicNerve Tissue ProteinsReceptors, ImmunologicRetinaRetinal NeovascularizationSignal TransductionConceptsOxygen-induced retinopathyPathological ocular neovascularizationCorneal neovascularizationMyeloid cellsOcular neovascularizationHeterogeneous population of myeloid cellsBlood-retina barrier integrityPopulation of myeloid cellsActivation of myeloid cellsMonoclonal antibodiesOcular neovascular diseasesBlinding eye diseaseHuman monoclonal antibodyExtracellular domainMouse model in vivoModel in vivoMAb treatmentMyeloid populationsOIR retinasNeovascular diseasesVision lossEye diseaseSlit-RoboSlit-Robo signalingBlocking antibodiesNotch signaling regulates UNC5B to suppress endothelial proliferation, migration, junction activity, and retinal plexus branching
Raza Q, Nadeem T, Youn S, Swaminathan B, Gupta A, Sargis T, Du J, Cuervo H, Eichmann A, Ackerman S, Naiche L, Kitajewski J. Notch signaling regulates UNC5B to suppress endothelial proliferation, migration, junction activity, and retinal plexus branching. Scientific Reports 2024, 14: 13603. PMID: 38866944, PMCID: PMC11169293, DOI: 10.1038/s41598-024-64375-z.Peer-Reviewed Original ResearchConceptsNotch signalingEndothelial cell behaviorEndothelial junctionsCell behaviorMultiple endothelial cell typesStabilization of endothelial junctionsNotch activationEndothelial Notch signalingTarget of Notch signalingTranscriptional activation complexEndothelial cell typesPlexus branchesVascular densityEndothelial proliferationBrain endotheliumMouse retinaIn vivo targetingEffector proteinsVascular outgrowthJunction activityNotch proteinsEndothelial cellsExcessive vascularizationDownstream effectorsEndothelial gene expressionVEGF-C prophylaxis favors lymphatic drainage and modulates neuroinflammation in a stroke model
Boisserand L, Geraldo L, Bouchart J, Kamouh M, Lee S, Sanganahalli B, Spajer M, Zhang S, Lee S, Parent M, Xue Y, Skarica M, Yin X, Guegan J, Boyé K, Leser F, Jacob L, Poulet M, Li M, Liu X, Velazquez S, Singhabahu R, Robinson M, Askenase M, Osherov A, Sestan N, Zhou J, Alitalo K, Song E, Eichmann A, Sansing L, Benveniste H, Hyder F, Thomas J. VEGF-C prophylaxis favors lymphatic drainage and modulates neuroinflammation in a stroke model. Journal Of Experimental Medicine 2024, 221: e20221983. PMID: 38442272, PMCID: PMC10913814, DOI: 10.1084/jem.20221983.Peer-Reviewed Original ResearchConceptsVascular endothelial growth factor-CDeep cervical lymph nodesCentral nervous systemEffect of vascular endothelial growth factor-CMeningeal lymphatic vesselsAmeliorated motor performanceCervical lymph nodesIschemic strokeVEGF-C overexpressionIncreased BDNF signalingAcute ischemic strokeBrain cellsIncreased CSF drainageIschemic stroke outcomesModel of ischemic strokeMouse model of ischemic strokeImmune surveillanceCSF drainageLymph nodesFluid drainageNucleus RNA sequencingLymphatic growthLymphatic drainageMouse modelBDNF signalingStromal Cell-SLIT3/Cardiomyocyte-ROBO1 Axis Regulates Pressure Overload-Induced Cardiac Hypertrophy
Liu X, Li B, Wang S, Zhang E, Schultz M, Touma M, Da Rocha A, Evans S, Eichmann A, Herron T, Chen R, Xiong D, Jaworski A, Weiss S, Si M. Stromal Cell-SLIT3/Cardiomyocyte-ROBO1 Axis Regulates Pressure Overload-Induced Cardiac Hypertrophy. Circulation Research 2024, 134: 913-930. PMID: 38414132, PMCID: PMC10977056, DOI: 10.1161/circresaha.122.321292.Peer-Reviewed Original ResearchConceptsTransverse aortic constrictionAortic constrictionPressure overloadCardiomyocyte hypertrophyVascular mural cellsCardiomyocyte hypertrophy in vitroDecreased left ventricular hypertrophyStimulate cardiomyocyte hypertrophyCongenital heart defectsCell-specific knockoutLeft ventricular functionAdverse cardiac remodelingVentricular pressure overloadCardiomyocyte-specific deletionMural cellsHypertrophy in vitroPressure overload stressCardiac stromal cellsMyocardial tissue samplesEffects in vitroIn vitro studiesHypertrophy-related genesHeart defectsRegulate cardiac developmentVentricular function
2023
Chylomicrons Regulate Lacteal Permeability and Intestinal Lipid Absorption
Zarkada G, Chen X, Zhou X, Lange M, Zeng L, Lv W, Zhang X, Li Y, Zhou W, Liu K, Chen D, Ricard N, Liao J, Kim Y, Benedito R, Claesson-Welsh L, Alitalo K, Simons M, Ju R, Li X, Eichmann A, Zhang F. Chylomicrons Regulate Lacteal Permeability and Intestinal Lipid Absorption. Circulation Research 2023, 133: 333-349. PMID: 37462027, PMCID: PMC10530007, DOI: 10.1161/circresaha.123.322607.Peer-Reviewed Original ResearchConceptsLymphatic endothelial cellsCell-cell junctionsCytoskeleton contractionMolecular biology approachesSmall GTPase Rac1Cytoskeletal contractilityBiology approachGTPase Rac1Stress fibersA SignalingPI3KLipid uptakePermeability regulationLymphatic permeabilityIntestinal lipid absorptionLEC junctionJunction openingEndothelial cellsLymphatic capillariesVEGFR-2Fundamental mechanismsLymphatic barrierLymphatic vesselsVascular endothelial growthLymphatic junctionsCCL21-CCR7 signaling promotes microglia/macrophage recruitment and chemotherapy resistance in glioblastoma
Geraldo L, Garcia C, Xu Y, Leser F, Grimaldi I, de Camargo Magalhães E, Dejaegher J, Solie L, Pereira C, Correia A, De Vleeschouwer S, Tavitian B, Canedo N, Mathivet T, Thomas J, Eichmann A, Lima F. CCL21-CCR7 signaling promotes microglia/macrophage recruitment and chemotherapy resistance in glioblastoma. Cellular And Molecular Life Sciences 2023, 80: 179. PMID: 37314567, PMCID: PMC10267017, DOI: 10.1007/s00018-023-04788-7.Peer-Reviewed Original ResearchConceptsMicroglia/macrophage recruitmentC chemokine receptor type 7CCL21-CCR7Central nervous systemMacrophage recruitmentTumor microenvironmentChemokine receptor type 7Fatal primary tumorMouse GBM modelsChemokine ligand 21Potential therapeutic targetVEGF-A productionTumor cell deathCCR7 expressionTherapeutic optionsPrimary tumorPoor survivalCurrent treatmentGBM patientsTumor cell migrationTherapeutic targetBrain cancerNervous systemChemotherapy resistanceLigand 21
2022
Mitochondrial dysfunction induces ALK5-SMAD2-mediated hypovascularization and arteriovenous malformations in mouse retinas
Zhang H, Li B, Huang Q, López-Giráldez F, Tanaka Y, Lin Q, Mehta S, Wang G, Graham M, Liu X, Park I, Eichmann A, Min W, Zhou J. Mitochondrial dysfunction induces ALK5-SMAD2-mediated hypovascularization and arteriovenous malformations in mouse retinas. Nature Communications 2022, 13: 7637. PMID: 36496409, PMCID: PMC9741628, DOI: 10.1038/s41467-022-35262-w.Peer-Reviewed Original ResearchConceptsMitochondrial dysfunctionThioredoxin 2Single-cell RNA-seq analysisRNA-seq analysisMutant miceNuclear genesMitochondrial proteinsMitochondrial localizationHuman retinal diseasesTranscriptional factorsGene expressionMutant retinasMitochondrial activityExtracellular matrixNovel mechanismVascular maturationArteriovenous malformationsGenetic deficiencyVessel growthSmad2Mouse retinaVascular malformationsMechanistic studiesBasement membraneRetinal vascular malformations
2021
Slit2-Robo Signaling Promotes Glomerular Vascularization and Nephron Development
Li J, Geraldo LH, Dubrac A, Zarkada G, Eichmann A. Slit2-Robo Signaling Promotes Glomerular Vascularization and Nephron Development. Journal Of The American Society Of Nephrology 2021, 32: 2255-2272. PMID: 34341180, PMCID: PMC8729857, DOI: 10.1681/asn.2020111640.Peer-Reviewed Original ResearchConceptsGlomerular vascularizationRobo receptorsKidney functionVascular developmentGlomerular perfusionKidney diseaseGlomerular endotheliumLigand trapInhibited vascularizationSlit2-RoboEndothelial proliferationGlomerular capillariesEndothelial compartmentGlomerular angiogenesisPerfusion analysisKidney vasculatureVascularizationUreteric bud branchingNovel roleAxon guidanceNephron developmentBlood filtrationReceptorsAngiogenesisGene deletion
2012
ALK1 Signaling Inhibits Angiogenesis by Cooperating with the Notch Pathway
Larrivée B, Prahst C, Gordon E, del Toro R, Mathivet T, Duarte A, Simons M, Eichmann A. ALK1 Signaling Inhibits Angiogenesis by Cooperating with the Notch Pathway. Developmental Cell 2012, 22: 489-500. PMID: 22421041, PMCID: PMC4047762, DOI: 10.1016/j.devcel.2012.02.005.Peer-Reviewed Original ResearchMeSH KeywordsActivin Receptors, Type IActivin Receptors, Type IIAnimalsArteriovenous MalformationsBasic Helix-Loop-Helix Transcription FactorsCell Cycle ProteinsDipeptidesDisease Models, AnimalGrowth Differentiation Factor 2Growth Differentiation FactorsHumansMiceMice, Inbred C57BLNeovascularization, PhysiologicReceptors, NotchRepressor ProteinsRetinaSignal TransductionSmad ProteinsTelangiectasia, Hereditary HemorrhagicVascular Endothelial Growth FactorsConceptsActivin receptor-like kinase 1Hereditary hemorrhagic telangiectasiaArteriovenous malformationsActivation of ALK1Receptor-like kinase 1Notch pathwayVascular lesionsHemorrhagic telangiectasiaPostnatal developmentInhibits angiogenesisNotch inhibitionTip cell formationReceptor familyAngiogenesisHypervascularizationALK1Kinase 1Cell formationEndothelial sproutingPatients
2011
Vascular endothelial growth factor receptor 3 directly regulates murine neurogenesis
Calvo CF, Fontaine RH, Soueid J, Tammela T, Makinen T, Alfaro-Cervello C, Bonnaud F, Miguez A, Benhaim L, Xu Y, Barallobre MJ, Moutkine I, Lyytikkä J, Tatlisumak T, Pytowski B, Zalc B, Richardson W, Kessaris N, Garcia-Verdugo JM, Alitalo K, Eichmann A, Thomas JL. Vascular endothelial growth factor receptor 3 directly regulates murine neurogenesis. Genes & Development 2011, 25: 831-844. PMID: 21498572, PMCID: PMC3078708, DOI: 10.1101/gad.615311.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCells, CulturedEnzyme-Linked Immunosorbent AssayImmunohistochemistryLymphangiogenesisMiceMice, Mutant StrainsMicroscopy, Electron, TransmissionNeovascularization, PhysiologicNeural Stem CellsNeurogenesisOligonucleotide Array Sequence AnalysisReverse Transcriptase Polymerase Chain ReactionVascular Endothelial Growth Factor Receptor-3ConceptsNeural stem cellsSubventricular zoneVEGF receptorsNeural cellsVEGFR-3Vascular endothelial growth factor (VEGF) familyEndothelial growth factor familyVascular endothelial growth factor receptor 3VEGFR-3 expressionMultipotent neural stem cellsCapillary endothelial cellsGrowth factor receptor 3Overexpression of VEGFGrowth factor familyAdult neurogenesisSVZ neurogenesisReporter miceReceptor 3NeurogenesisNeurodegenerative diseasesConditional deletionEndothelial cellsGrowth factorLigand VEGFInducible deletionRobo4 Maintains Vessel Integrity and Inhibits Angiogenesis by Interacting with UNC5B
Koch AW, Mathivet T, Larrivée B, Tong RK, Kowalski J, Pibouin-Fragner L, Bouvrée K, Stawicki S, Nicholes K, Rathore N, Scales SJ, Luis E, del Toro R, Freitas C, Bréant C, Michaud A, Corvol P, Thomas JL, Wu Y, Peale F, Watts RJ, Tessier-Lavigne M, Bagri A, Eichmann A. Robo4 Maintains Vessel Integrity and Inhibits Angiogenesis by Interacting with UNC5B. Developmental Cell 2011, 20: 33-46. PMID: 21238923, DOI: 10.1016/j.devcel.2010.12.001.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodies, BlockingBlood VesselsCapillary PermeabilityEnzyme ActivationHumansLigandsMiceModels, BiologicalNeovascularization, PathologicNerve Tissue ProteinsNetrin ReceptorsProtein BindingReceptors, Cell SurfaceReceptors, ImmunologicRetinal VesselsSignal TransductionSrc-Family KinasesSus scrofaVascular Endothelial Growth Factor AConceptsProtein-protein interaction screenVascular endothelial growth factorFunction-blocking monoclonal antibodiesInteraction screenNovel functionGuidance receptorsExtracellular domainNetrin receptorsReceptor familyVessel integrityReceptor interactionInhibits angiogenesisRobo4Unexpected interactionsGrowth factorEndothelial cellsUNC5BVascular integrityEndothelial growth factorAngiogenesisIncreases angiogenesisReceptorsMonoclonal antibodiesIntegrityProtein
2007
The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching
Suchting S, Freitas C, le Noble F, Benedito R, Bréant C, Duarte A, Eichmann A. The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching. Proceedings Of The National Academy Of Sciences Of The United States Of America 2007, 104: 3225-3230. PMID: 17296941, PMCID: PMC1805603, DOI: 10.1073/pnas.0611177104.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAmyloid Precursor Protein SecretasesAnimalsCalcium-Binding ProteinsEndothelium, VascularGamma-Aminobutyric AcidImmunohistochemistryIn Situ HybridizationIntracellular Signaling Peptides and ProteinsMembrane ProteinsMiceMice, Mutant StrainsReceptors, Vascular Endothelial Growth FactorRetinal VesselsSignal TransductionTriglyceridesVascular Endothelial Growth Factor AConceptsTip cell formationEndothelial tip cell formationTip cellsNotch ligand DeltaCell formationCell marker genesEndothelial tip cellsVessel branchingLigand DeltaExpression of Dll4Vascular network formationTransmembrane ligandsNotch receptorsMarker genesNegative regulatorAngiogenic sproutingVEGF receptor 2VEGF stimulationFilopodia extensionGamma-secretase inhibitorsGrowth factor VEGFVascular sproutingPharmacological inhibitionDll4Heterozygous deletion
2004
The netrin receptor UNC5B mediates guidance events controlling morphogenesis of the vascular system
Lu X, le Noble F, Yuan L, Jiang Q, de Lafarge B, Sugiyama D, Bréant C, Claes F, De Smet F, Thomas JL, Autiero M, Carmeliet P, Tessier-Lavigne M, Eichmann A. The netrin receptor UNC5B mediates guidance events controlling morphogenesis of the vascular system. Nature 2004, 432: 179-186. PMID: 15510105, DOI: 10.1038/nature03080.Peer-Reviewed Original ResearchConceptsNetrin receptor UNC5BEndothelial tip cell filopodiaTip cell filopodiaReceptor UNC5BEndothelial tip cellsVascular systemNetrin-1aTip cellsEndothelial cellsProper wiringAxon guidanceCell filopodiaNetrin receptorsGuidance eventsFilopodial retractionMorphogenesisUNC5BVessel branchingAberrant extensionAnatomical similaritiesNetrin-1CellsZebrafishGenesGuidance functionRetinoic acid controls blood vessel formation by modulating endothelial and mural cell interaction via suppression of Tie2 signaling in vascular progenitor cells
Suzuki Y, Komi Y, Ashino H, Yamashita J, Inoue J, Yoshiki A, Eichmann A, Amanuma H, Kojima S. Retinoic acid controls blood vessel formation by modulating endothelial and mural cell interaction via suppression of Tie2 signaling in vascular progenitor cells. Blood 2004, 104: 166-169. PMID: 15026310, DOI: 10.1182/blood-2003-09-3293.Peer-Reviewed Original ResearchConceptsVascular progenitor cellsAll-trans retinoic acidChicken chorioallantoic membraneEndothelial cellsTie2 signalingProgenitor cellsBlood vessel formationMural cellsEpithelial layerExpression of angiopoietin-2Vessel formationRetinoic acidImpaired vascular remodelingImpaired branchingAngiopoietin-2Ang-1Vascular remodelingRo41-5253Cell interactionsMural cell interactions
2001
A model for gene therapy of human hereditary lymphedema
Karkkainen M, Saaristo A, Jussila L, Karila K, Lawrence E, Pajusola K, Bueler H, Eichmann A, Kauppinen R, Kettunen M, Ylä-Herttuala S, Finegold D, Ferrell R, Alitalo K. A model for gene therapy of human hereditary lymphedema. Proceedings Of The National Academy Of Sciences Of The United States Of America 2001, 98: 12677-12682. PMID: 11592985, PMCID: PMC60113, DOI: 10.1073/pnas.221449198.Peer-Reviewed Original ResearchMeSH KeywordsAdenoviridaeAmino Acid SequenceAnimalsDependovirusDisease Models, AnimalEndothelial Growth FactorsGenetic TherapyHumansLymphedemaMaleMiceMice, Inbred BALB CMice, Inbred C3HMolecular Sequence DataNerve Tissue ProteinsNeuropilin-1Receptor Protein-Tyrosine KinasesReceptors, Growth FactorVascular Endothelial Growth Factor CVascular Endothelial Growth Factor Receptor-3
2000
Developmental expression of Pim kinases suggests functions also outside of the hematopoietic system
Eichmann A, Yuan L, Bréant C, Alitalo K, Koskinen P. Developmental expression of Pim kinases suggests functions also outside of the hematopoietic system. Oncogene 2000, 19: 1215-1224. PMID: 10713710, DOI: 10.1038/sj.onc.1203355.Peer-Reviewed Original ResearchMeSH KeywordsAbdomenAmino Acid SequenceAnimalsCloning, MolecularEctodermEmbryo, NonmammalianEmbryonic and Fetal DevelopmentEmbryonic DevelopmentGene Expression Regulation, DevelopmentalHematopoiesisHumansMiceMolecular Sequence DataNervous SystemOrgan SpecificityProtein Serine-Threonine KinasesProto-Oncogene ProteinsProto-Oncogene Proteins c-pim-1QuailRatsTranscription, GeneticConceptsExpression patternsSerine/threonine kinaseDeduced amino acid sequenceDynamic expression patternHematopoietic systemPim-1Amino acid sequencePim family kinasesEarly developmental stagesFunctional redundancyThreonine kinaseFamily kinasesEmbryonic developmentStrong homologyNovel functionAcid sequenceExpression sitesPIM genesAvian embryosDevelopmental expressionDevelopmental stagesPIM familyPIM kinasesCDNAKinase
1998
Segregation of the embryonic vascular and hemopoietic systems
Eichmann A, Corbel C, Le Douarin N. Segregation of the embryonic vascular and hemopoietic systems. Biochemistry And Cell Biology 1998, 76: 939-946. PMID: 10392707, DOI: 10.1139/o98-106.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBrainCell DifferentiationChick EmbryoEmbryo, NonmammalianEndothelial Growth FactorsEndothelium, VascularHematopoietic Stem CellsLymphokinesMesodermMiceModels, CardiovascularQuailReceptor Protein-Tyrosine KinasesReceptors, Growth FactorReceptors, Vascular Endothelial Growth FactorVascular Endothelial Growth Factor AVascular Endothelial Growth FactorsConceptsEndothelial precursor cellsAvian embryosPrecursor cellsVEGF receptor VEGFR2Primary vascular systemEndothelial cellsGastrulation stageGrowth factorDevelopmental biologyVertebrate classesSpecific growth factorsVascular endothelial growth factorAngiogenic vascular endothelial growth factorMouse embryosMolecular mechanismsCognate receptorsSubsequent assemblyHemopoietic cellsEmbryosReceptor VEGFR2Hemopoietic systemCulture experimentsVEGFR2CellsSignificant insightsAvian VEGF-C: cloning, embryonic expression pattern and stimulation of the differentiation of VEGFR2-expressing endothelial cell precursors
Eichmann A, Corbel C, Jaffredo T, Bréant C, Joukov V, Kumar V, Alitalo K, le Douarin N. Avian VEGF-C: cloning, embryonic expression pattern and stimulation of the differentiation of VEGFR2-expressing endothelial cell precursors. Development 1998, 125: 743-752. PMID: 9435294, DOI: 10.1242/dev.125.4.743.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsBase SequenceCell DifferentiationCloning, MolecularDNA, ComplementaryEndothelial Growth FactorsEndothelium, VascularGene Expression Regulation, DevelopmentalIn Situ HybridizationMesodermMiceMolecular Sequence DataProtein BindingQuailReceptor Protein-Tyrosine KinasesReceptors, Cell SurfaceReceptors, Growth FactorReceptors, Vascular Endothelial Growth FactorRecombinant ProteinsSequence Homology, Amino AcidStem CellsVascular Endothelial Growth Factor CVascular Endothelial Growth Factor Receptor-3
1997
The expression pattern of the mafB/kr gene in birds and mice reveals that the kreisler phenotype does not represent a null mutant
Eichmann A, Grapin-Botton A, Kelly L, Graf T, Le Douarin N, Sieweke M. The expression pattern of the mafB/kr gene in birds and mice reveals that the kreisler phenotype does not represent a null mutant. Cells And Development 1997, 65: 111-122. PMID: 9256349, DOI: 10.1016/s0925-4773(97)00063-4.Peer-Reviewed Original ResearchLigand-dependent development of the endothelial and hemopoietic lineages from embryonic mesodermal cells expressing vascular endothelial growth factor receptor 2
Eichmann A, Corbel C, Nataf V, Vaigot P, Bréant C, Le Douarin N. Ligand-dependent development of the endothelial and hemopoietic lineages from embryonic mesodermal cells expressing vascular endothelial growth factor receptor 2. Proceedings Of The National Academy Of Sciences Of The United States Of America 1997, 94: 5141-5146. PMID: 9144204, PMCID: PMC24645, DOI: 10.1073/pnas.94.10.5141.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodies, MonoclonalCell DifferentiationChick EmbryoEndothelial Growth FactorsEndothelium, VascularGastrulaHematopoietic Stem CellsHomozygoteLigandsLymphokinesMesodermMiceMice, Inbred BALB CMice, KnockoutQuailReceptor Protein-Tyrosine KinasesReceptors, Growth FactorReceptors, Vascular Endothelial Growth FactorVascular Endothelial Growth Factor AVascular Endothelial Growth FactorsConceptsVascular endothelial growth factor receptor 2VEGFR2 ligandsEndothelial growth factor receptor 2Embryonic mesodermal cellsVascular endothelial lineageHemopoietic cellsDevelopmental decisionsGastrulation stageHomozygous null miceMesodermal cellsAbsence of VEGFGene productsGene targetingNull mutationEndothelial lineageHemopoietic differentiationExtracellular domainClonal culturesLineagesHemopoietic lineagesEndothelial differentiationEndothelial cell coloniesCell coloniesCell microenvironmentGrowth factor receptor 2