2022
Vascular pathobiology of pulmonary hypertension
Gallardo-Vara E, Ntokou A, Dave J, Jovin D, Saddouk F, Greif D. Vascular pathobiology of pulmonary hypertension. The Journal Of Heart And Lung Transplantation 2022, 42: 544-552. PMID: 36604291, PMCID: PMC10121751, DOI: 10.1016/j.healun.2022.12.012.Peer-Reviewed Original ResearchConceptsPulmonary hypertensionCell typesSmooth muscle cell proliferationEndothelial cell dysfunctionMuscle cell proliferationKruppel-like factor 4Extracellular matrix remodelingHypoxia-inducible factorBox proteinBlood pressurePulmonary arteryInflammatory cellsPulmonary vasculatureMain cell typesVascular pathogenesisVasoactive moleculesCell dysfunctionClinical impactVascular pathobiologyPathological remodelingIntercellular crosstalkLethal diseaseMesenchymal transitionMatrix remodelingGrowth factor
2021
Distinct roles of KLF4 in mesenchymal cell subtypes during lung fibrogenesis
Chandran RR, Xie Y, Gallardo-Vara E, Adams T, Garcia-Milian R, Kabir I, Sheikh AQ, Kaminski N, Martin KA, Herzog EL, Greif DM. Distinct roles of KLF4 in mesenchymal cell subtypes during lung fibrogenesis. Nature Communications 2021, 12: 7179. PMID: 34893592, PMCID: PMC8664937, DOI: 10.1038/s41467-021-27499-8.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell ProliferationDisease Models, AnimalDown-RegulationExtracellular MatrixFemaleFibroblastsFibrosisHumansKruppel-Like Factor 4LungLung InjuryMaleMesenchymal Stem CellsMiceMice, Inbred C57BLMyofibroblastsReceptor, Platelet-Derived Growth Factor betaRespiratory Tract DiseasesSignal TransductionTransforming Growth Factor betaConceptsMesenchymal cell typesPlatelet-derived growth factor receptorSmooth muscle actinLung fibrosisKruppel-like factor 4Forkhead box M1Growth factor receptorCell transitionCell typesExtracellular matrixDistinct rolesKLF4Box M1C chemokine ligandMesenchymal cell subtypesFactor receptorPro-fibrotic effectsFactor 4PDGFRMesenchymeCellsMacrophage accumulationKLF4 levelsChemokine ligandLung fibrogenesis
2018
NCK-dependent pericyte migration promotes pathological neovascularization in ischemic retinopathy
Dubrac A, Künzel SE, Künzel SH, Li J, Chandran RR, Martin K, Greif DM, Adams RH, Eichmann A. NCK-dependent pericyte migration promotes pathological neovascularization in ischemic retinopathy. Nature Communications 2018, 9: 3463. PMID: 30150707, PMCID: PMC6110853, DOI: 10.1038/s41467-018-05926-7.Peer-Reviewed Original ResearchConceptsNeovascular tuftsPericyte migrationMural cellsPathological neovascular tuftsPDGF-B overexpressionTreatment of retinopathyOxygen-induced retinopathyCapillary barrier functionΑ-SMA expressionPlatelet-derived growth factor receptorPlatelet-derived growth factorPhosphorylation of PDGFRβGrowth factor receptorIschemic retinopathyProliferative retinopathyEndothelial-specific knockoutVascular leakagePericyte depletionPathological neovascularizationGenetic lineage tracingMouse modelPericyte proliferationNck2 adaptor proteinRetinopathyBarrier functionPericyte ALK5/TIMP3 Axis Contributes to Endothelial Morphogenesis in the Developing Brain
Dave JM, Mirabella T, Weatherbee SD, Greif DM. Pericyte ALK5/TIMP3 Axis Contributes to Endothelial Morphogenesis in the Developing Brain. Developmental Cell 2018, 44: 665-678.e6. PMID: 29456135, PMCID: PMC5871595, DOI: 10.1016/j.devcel.2018.01.018.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlood-Brain BarrierBrainEmbryo, MammalianEndothelium, VascularFemaleHumansIntracranial HemorrhagesMaleMiceMice, Inbred C57BLMice, KnockoutMorphogenesisPericytesProtein Serine-Threonine KinasesReceptor, Transforming Growth Factor-beta Type IReceptors, Transforming Growth Factor betaSignal TransductionTissue Inhibitor of Metalloproteinase-3ConceptsEndothelial morphogenesisReceptor-like kinasesBlood-brain barrierActivin receptor-like kinaseGerminal matrixGerminal matrix hemorrhage-intraventricular hemorrhageMurine embryosEC morphogenesisEndothelial cellsEC hyperproliferationMorphogenesisMatrix metalloproteinase-3Glial precursorsBasement membrane collagenMatrix metalloproteinase activityBBB developmentMutantsVascular stabilityALK5Brain pericytesAbnormal dilationSubstantial therapeutic potentialMetalloproteinase-3Membrane collagenTissue inhibitor
2016
Integrin β3 inhibition is a therapeutic strategy for supravalvular aortic stenosis
Misra A, Sheikh AQ, Kumar A, Luo J, Zhang J, Hinton RB, Smoot L, Kaplan P, Urban Z, Qyang Y, Tellides G, Greif DM. Integrin β3 inhibition is a therapeutic strategy for supravalvular aortic stenosis. Journal Of Experimental Medicine 2016, 213: 451-463. PMID: 26858344, PMCID: PMC4813675, DOI: 10.1084/jem.20150688.Peer-Reviewed Original ResearchConceptsSmooth muscle cellsMutant miceTherapeutic strategiesAortic stenosis patientsAortic smooth muscle cellsSupravalvular aortic stenosisAttractive therapeutic strategyIntegrin β3 levelsAortic pathologyAortic stenosisStenosis patientsArterial diseaseLumen lossPathological featuresArterial mediaLarge arteriesAortic mediaElastin deficiencyPharmacological inhibitionMuscle cellsStenosisMicePathological stenosisExplant culturesSVAS patients
2012
An endothelial apelin-FGF link mediated by miR-424 and miR-503 is disrupted in pulmonary arterial hypertension
Kim J, Kang Y, Kojima Y, Lighthouse JK, Hu X, Aldred MA, McLean DL, Park H, Comhair SA, Greif DM, Erzurum SC, Chun HJ. An endothelial apelin-FGF link mediated by miR-424 and miR-503 is disrupted in pulmonary arterial hypertension. Nature Medicine 2012, 19: 74-82. PMID: 23263626, PMCID: PMC3540168, DOI: 10.1038/nm.3040.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApelinCell MovementCell ProliferationCells, CulturedCulture Media, ConditionedDown-RegulationEndothelial CellsFamilial Primary Pulmonary HypertensionFibroblast Growth Factor 2HumansHypertension, PulmonaryIntercellular Signaling Peptides and ProteinsMiceMice, Inbred C57BLMice, KnockoutMicroRNAsMuscle, Smooth, VascularMyocytes, Smooth MusclePulmonary ArteryRatsReceptor, Fibroblast Growth Factor, Type 1RNA InterferenceRNA, Small InterferingSignal TransductionVascular DiseasesConceptsPulmonary arterial hypertensionArterial hypertensionVascular smooth muscle cellsPulmonary endothelial cellsSmooth muscle cellsEndothelial cell proliferationPulmonary hypertensionPeptide apelinCytokine productionRat modelVascular homeostasisHypertensionMiR-503MiR-424Endothelial cellsCell proliferationRadial Construction of an Arterial Wall
Greif DM, Kumar M, Lighthouse JK, Hum J, An A, Ding L, Red-Horse K, Espinoza FH, Olson L, Offermanns S, Krasnow MA. Radial Construction of an Arterial Wall. Developmental Cell 2012, 23: 482-493. PMID: 22975322, PMCID: PMC3500096, DOI: 10.1016/j.devcel.2012.07.009.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell DivisionLungMesodermMiceMice, TransgenicProto-Oncogene Proteins c-sisPulmonary ArteryRadial ArterySignal TransductionConceptsInner layer cellsCoordinated processGenetic analysisSuccessive cell layersVessel-specific differencesSignaling pathwaysCell reorientationSequential inductionEndothelial tubesSignal gradientMuscle cellsSignal contributesSerious diseaseCellsCell layerLayer cellsRadial migrationMesenchymeConcentric layersPathwayArterial wallPDGFInvasionInductionArtery wall
2010
Targeting Robo4-Dependent Slit Signaling to Survive the Cytokine Storm in Sepsis and Influenza
London NR, Zhu W, Bozza FA, Smith MC, Greif DM, Sorensen LK, Chen L, Kaminoh Y, Chan AC, Passi SF, Day CW, Barnard DL, Zimmerman GA, Krasnow MA, Li DY. Targeting Robo4-Dependent Slit Signaling to Survive the Cytokine Storm in Sepsis and Influenza. Science Translational Medicine 2010, 2: 23ra19. PMID: 20375003, PMCID: PMC2875996, DOI: 10.1126/scitranslmed.3000678.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCadherinsCapillary PermeabilityCateninsCell LineCytokinesDelta CateninDisease Models, AnimalEndothelium, VascularHumansInfluenza A Virus, H5N1 SubtypeIntercellular Signaling Peptides and ProteinsLipopolysaccharidesMiceMice, Inbred C57BLNerve Tissue ProteinsOrthomyxoviridae InfectionsProtein BindingProtein StabilityProtein TransportReceptors, Cell SurfaceReceptors, ImmunologicSepsisSignal TransductionConceptsInnate immune responseImmune systemCytokine stormImmune responseInfectious agentsHost innate immune responseCurrent medical therapyMultiple inflammatory cytokinesBacterial endotoxin exposureHost immune systemInnate immune systemMultiple infectious agentsAdditional immune responsesPolymicrobial sepsisMedical therapyOrgan failureInflammatory cytokinesCytokine releaseTumor necrosisEndotoxin exposureTissue edemaInterleukin-1betaVascular permeabilityTherapeutic strategiesAnimal models
2002
Site-Specific Dephosphorylation of Endothelial Nitric Oxide Synthase by Protein Phosphatase 2A: Evidence for Crosstalk between Phosphorylation Sites †
Greif DM, Kou R, Michel T. Site-Specific Dephosphorylation of Endothelial Nitric Oxide Synthase by Protein Phosphatase 2A: Evidence for Crosstalk between Phosphorylation Sites †. Biochemistry 2002, 41: 15845-15853. PMID: 12501214, DOI: 10.1021/bi026732g.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCattleCell LineCOS CellsEnzyme ActivationEnzyme InhibitorsMarine ToxinsMutagenesis, Site-DirectedNitric Oxide SynthaseNitric Oxide Synthase Type IIIOkadaic AcidOxazolesPhosphatesPhosphoprotein PhosphatasesPhosphorus RadioisotopesPhosphorylationProtein Phosphatase 2SerineSignal TransductionThreonineTransfectionConceptsProtein phosphatase 2ASerine 116Bovine aortic endothelial cellsCOS-7 cellsENOS dephosphorylationENOS mutantPhosphatase 2ASerine 1179Phosphorylation sitesThreonine 497Calcium/calmodulin-dependent enzymesInhibitor of PP2ASite-specific dephosphorylationProtein kinase pathwayWild-type eNOSEnzyme activityNitric oxide-dependent signaling pathwaysCalmodulin-dependent enzymesProtein phosphatasePosttranslational modificationsEpitope tagENOS phosphorylationKinase pathwayEndothelial cellsRecombinant proteins