2024
Loss of TGFβ-Mediated Repression of Angiopoietin-2 in Pericytes Underlies Germinal Matrix Hemorrhage Pathogenesis
Dave J, Chakraborty R, Agyemang A, Ntokou A, Saito J, Ballabh P, Martin K, Greif D. Loss of TGFβ-Mediated Repression of Angiopoietin-2 in Pericytes Underlies Germinal Matrix Hemorrhage Pathogenesis. Stroke 2024, 55: 2340-2352. PMID: 39129597, PMCID: PMC11347087, DOI: 10.1161/strokeaha.123.045248.Peer-Reviewed Original ResearchAngiopoietin-2Germinal matrix hemorrhage-intraventricular hemorrhagePerinatal lethalityEndothelial cell hyperproliferationEndothelial cellsBrain pericytesGenetic inhibitionVascular cellsBlood-brain barrier integrityBlood-brain barrier developmentBrain vascular cellsAbnormal vessel morphologyVessel morphologyProlonged survivalRegulating cross-talkMutant endothelial cellsHuman brain pericytesGerminal matrixCell hyperproliferationPhosphorylates Tie2Embryonic miceCellular sourceBarrier integrityGenetic ablationTherapeutic effectEndothelial HIFα-PDGF-B to smooth muscle Beclin1 signaling sustains pathological muscularization in pulmonary hypertension
Saddouk F, Kuzemczak A, Saito J, Greif D. Endothelial HIFα-PDGF-B to smooth muscle Beclin1 signaling sustains pathological muscularization in pulmonary hypertension. JCI Insight 2024, 9: e162449. PMID: 38652543, PMCID: PMC11141934, DOI: 10.1172/jci.insight.162449.Peer-Reviewed Original ResearchSmooth muscle cellsArteriole smooth muscle cellsPulmonary hypertensionPlatelet-derived growth factor-BDistal muscularizationSugen 5416Endothelial cellsHuman idiopathic pulmonary arterial hypertensionHypoxia-induced pulmonary vascular remodelingPulmonary artery smooth muscle cellsIdiopathic pulmonary arterial hypertensionHypoxia-inducible factor (HIF)-1aArtery smooth muscle cellsDistal pulmonary arteriolesPulmonary arterial hypertensionPulmonary vascular remodelingDeletion of Hif1aLung endothelial cellsGrowth factor BEC-specific deletionPulmonary arteriolesArterial hypertensionLung lysatesMuscle cellsVascular remodeling
2022
JAGGED1/NOTCH3 activation promotes aortic hypermuscularization and stenosis in elastin deficiency
Dave JM, Chakraborty R, Ntokou A, Saito J, Saddouk FZ, Feng Z, Misra A, Tellides G, Riemer RK, Urban Z, Kinnear C, Ellis J, Mital S, Mecham R, Martin KA, Greif DM. JAGGED1/NOTCH3 activation promotes aortic hypermuscularization and stenosis in elastin deficiency. Journal Of Clinical Investigation 2022, 132: e142338. PMID: 34990407, PMCID: PMC8884911, DOI: 10.1172/jci142338.Peer-Reviewed Original ResearchConceptsSmooth muscle cellsSupravalvular aortic stenosisEndothelial cellsElastin insufficiencyObstructive arterial diseaseAortic smooth muscle cellsΓ-secretaseAortic vascular cellsPotential therapeutic targetNotch3 intracellular domainNotch ligand Jagged1Aortic stenosisArterial diseasePathological featuresPharmacological treatmentJag1 deletionLuminal obstructionMouse modelNotch3 activationTherapeutic targetSMC accumulationPathway upregulationAortic samplesMice displayNotch3 deletion
2018
Cell Autonomous and Non-cell Autonomous Regulation of SMC Progenitors in Pulmonary Hypertension
Sheikh AQ, Saddouk FZ, Ntokou A, Mazurek R, Greif DM. Cell Autonomous and Non-cell Autonomous Regulation of SMC Progenitors in Pulmonary Hypertension. Cell Reports 2018, 23: 1152-1165. PMID: 29694892, PMCID: PMC5959296, DOI: 10.1016/j.celrep.2018.03.043.Peer-Reviewed Original ResearchConceptsPulmonary hypertensionMyeloid cellsPlatelet-derived growth factor receptor βGrowth factor receptor βKruppel-like factor 4Muscle cell markersAttractive therapeutic targetHypoxia-inducible factor-1Vascular muscularizationDistal migrationNormal lungSmall arteriolesMuscle expansionHypertensionTherapeutic targetNon-cell autonomous pathwaysReceptor βCell expressionCell inductionCell markersSMC progenitorsEndothelial cellsFactor 1Factor 4MuscularizationPericyte 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
2017
Using In Vivo and Tissue and Cell Explant Approaches to Study the Morphogenesis and Pathogenesis of the Embryonic and Perinatal Aorta.
Misra A, Feng Z, Zhang J, Lou ZY, Greif DM. Using In Vivo and Tissue and Cell Explant Approaches to Study the Morphogenesis and Pathogenesis of the Embryonic and Perinatal Aorta. Journal Of Visualized Experiments 2017 PMID: 28930997, PMCID: PMC5752224, DOI: 10.3791/56039.Peer-Reviewed Original ResearchConceptsSmooth muscle cellsAortic smooth muscle cellsPregnant micePharmacological agentsAortic wallAortaLarge arteriesAdult aortaMuscle cellsEndothelial cellsPathological modelsHypothesis-generating experimentsContinuous exposureCell explantsTissue explantsPathogenesisFate mappingSpecific gene targetsClonal analysisNormal developmentVivoGene targetsExtracellular matrixClonal architectureCellsWhere do new endothelial cells come from in the injured heart?
Greif DM, Eichmann A. Where do new endothelial cells come from in the injured heart? Nature Reviews Cardiology 2017, 14: 507-508. PMID: 28770866, DOI: 10.1038/nrcardio.2017.121.Commentaries, Editorials and Letters
2013
Development and pathologies of the arterial wall
Seidelmann SB, Lighthouse JK, Greif DM. Development and pathologies of the arterial wall. Cellular And Molecular Life Sciences 2013, 71: 1977-1999. PMID: 24071897, PMCID: PMC11113178, DOI: 10.1007/s00018-013-1478-y.Peer-Reviewed Original ResearchMeSH KeywordsAngiogenic ProteinsAnimalsArteriesCardiovascular DiseasesCell DifferentiationCell LineageEndothelial CellsEndothelium, VascularGene Expression Regulation, DevelopmentalHumansMorphogenesisMuscle, Smooth, VascularMyocytes, Smooth MuscleNeovascularization, PathologicNeovascularization, PhysiologicConceptsAdventitial progenitor cellsDevastating vascular diseaseDevelopmental biologyWall developmentSmooth muscle cell originHuman diseasesExtracellular matrixMuscle cell originProcess of angiogenesisProgenitor cellsEndothelial networksDisease mechanismsNovel therapeutic strategiesDevelopmental studiesEndothelial cellsSmooth muscleCellsMorphogenesisTherapeutic strategiesCell originBiologyDifferentiationVascular diseaseVascular wallVascular wall abnormalities
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 proliferation
2004
KLF2 Is a Novel Transcriptional Regulator of Endothelial Proinflammatory Activation
SenBanerjee S, Lin Z, Atkins GB, Greif DM, Rao RM, Kumar A, Feinberg MW, Chen Z, Simon DI, Luscinskas FW, Michel TM, Gimbrone MA, García-Cardeña G, Jain MK. KLF2 Is a Novel Transcriptional Regulator of Endothelial Proinflammatory Activation. Journal Of Experimental Medicine 2004, 199: 1305-1315. PMID: 15136591, PMCID: PMC2211816, DOI: 10.1084/jem.20031132.Peer-Reviewed Original ResearchMeSH KeywordsBase SequenceCells, CulturedDNA PrimersE-SelectinEndothelium, VascularGene Expression RegulationGlutathione TransferaseHumansInflammationIntercellular Adhesion Molecule-1Interleukin-1Kruppel-Like Transcription FactorsNF-kappa BNitric Oxide SynthaseNitric Oxide Synthase Type IIIOligonucleotide Array Sequence AnalysisPolymerase Chain ReactionPromoter Regions, GeneticStress, MechanicalTrans-ActivatorsTranscription, GeneticUmbilical VeinsZinc FingersConceptsUmbilical vein endothelial cellsVein endothelial cellsProinflammatory cytokinesEndothelial nitric oxide synthase expressionVascular cell adhesion molecule-1Nitric oxide synthase expressionInflammatory cytokines interleukin-1betaEndothelial cellsCell adhesion molecule-1Endothelial proinflammatory activationOxide synthase expressionCultured human umbilical vein endothelial cellsCytokine interleukin-1betaVascular disease statesEndothelial adhesion molecules EAdhesion molecule-1Adhesion molecules EOverexpression of KLF2Human umbilical vein endothelial cellsAMP response element binding proteinCyclic AMP response element binding proteinResponse element-binding proteinT cell attachmentEndothelial functionEndothelial activationCalmodulin phosphorylation and modulation of endothelial nitric oxide synthase catalysis
Greif DM, Sacks DB, Michel T. Calmodulin phosphorylation and modulation of endothelial nitric oxide synthase catalysis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2004, 101: 1165-1170. PMID: 14736917, PMCID: PMC337024, DOI: 10.1073/pnas.0306377101.Peer-Reviewed Original ResearchConceptsPhosphorylation of CaMBovine aortic endothelial cellsCaM phosphorylationCaM mutantsCalcium regulatory protein calmodulinBiosynthetic labelingRegulation of eNOSProtein kinase pathwayEndothelial NO synthaseSer-81Regulatory protein calmodulinKinase CK2Kinase pathwayEndothelial cellsCK2Protein calmodulinMutantsCalmodulin phosphorylationPhosphorylationAortic endothelial cellsPhenyl-SepharoseUnique pathwayENOS activationMutant CaMPathway
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 proteinsDephosphorylation of Endothelial Nitric-oxide Synthase by Vascular Endothelial Growth Factor IMPLICATIONS FOR THE VASCULAR RESPONSES TO CYCLOSPORIN A*
Kou R, Greif D, Michel T. Dephosphorylation of Endothelial Nitric-oxide Synthase by Vascular Endothelial Growth Factor IMPLICATIONS FOR THE VASCULAR RESPONSES TO CYCLOSPORIN A*. Journal Of Biological Chemistry 2002, 277: 29669-29673. PMID: 12050171, DOI: 10.1074/jbc.m204519200.Peer-Reviewed Original ResearchConceptsENOS dephosphorylationSerine 116MAP kinase pathway inhibitor U0126Protein phosphatase pathwaysPhosphorylation-deficient mutantDependent protein phosphatasePhosphorylation state-specific antibodiesWild-type enzymeVascular endothelial growth factorProtein kinase C inhibitor calphostinPathway inhibitor U0126Activation of calcineurinProtein phosphataseInhibitor of calcineurinPhosphatase pathwaysENOS agonistsProtein kinaseEndothelial cellsAlanine residuesDephosphorylationDependent enzymesInhibitor U0126Dephosphorylation of eNOSCultured endothelial cellsEnzyme activity