2024
Endothelial 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 remodelingDedifferentiated early postnatal lung myofibroblasts redifferentiate in adult disease
Chandran R, Adams T, Kabir I, Gallardo-Vara E, Kaminski N, Gomperts B, Greif D. Dedifferentiated early postnatal lung myofibroblasts redifferentiate in adult disease. Frontiers In Cell And Developmental Biology 2024, 12: 1335061. PMID: 38572485, PMCID: PMC10987733, DOI: 10.3389/fcell.2024.1335061.Peer-Reviewed Original ResearchRNA sequencing analysisSMA+ myofibroblastsGene expression profilesLung myofibroblastsAdult lungSequence analysisResponse to lung injurySingle cell RNA sequencing analysisTissue remodeling genesSmooth muscle cell markersLung to hypoxiaExpression profilesRemodeling genesMuscle cell markersResponse to injuryCell typesSMA cellsLineage tracingLung injuryCell markersLineagesGenesAdult diseaseDrug bleomycinLung surface areaHeterogeneity of hepatocyte dynamics restores liver architecture after chemical, physical or viral damage
Ruz-Maldonado I, Gonzalez J, Zhang H, Sun J, Bort A, Kabir I, Kibbey R, Suárez Y, Greif D, Fernández-Hernando C. Heterogeneity of hepatocyte dynamics restores liver architecture after chemical, physical or viral damage. Nature Communications 2024, 15: 1247. PMID: 38341404, PMCID: PMC10858916, DOI: 10.1038/s41467-024-45439-0.Peer-Reviewed Original ResearchManifestations of human atherosclerosis across vascular beds
Jovin D, Sumpio B, Greif D. Manifestations of human atherosclerosis across vascular beds. JVS-Vascular Insights 2024, 2: 100089. DOI: 10.1016/j.jvsvi.2024.100089.Peer-Reviewed Original ResearchVascular bedClinical managementCarotid arteryCommon risk factorsPeripheral arterial diseaseManagement of carotidClinical management of atherosclerosisEtiology of mortalityIntervention outcomesModel of atherogenesisPathology of atherosclerotic lesionsMedical therapyMeta-analysesTreatment responseFibrotic componentManagement of atherosclerosisLower extremitiesMale sexClinical studiesArtery diseaseMetabolic factorsPeripheral atherosclerosisRisk factorsIndividual patientsVascular territories
2023
Presenilin-1 in smooth muscle cells facilitates hypermuscularization in elastin aortopathy
Saito J, Dave J, Lau F, Greif D. Presenilin-1 in smooth muscle cells facilitates hypermuscularization in elastin aortopathy. IScience 2023, 27: 108636. PMID: 38226162, PMCID: PMC10788461, DOI: 10.1016/j.isci.2023.108636.Peer-Reviewed Original ResearchThe age of bone marrow dictates the clonality of smooth muscle-derived cells in atherosclerotic plaques
Kabir I, Zhang X, Dave J, Chakraborty R, Qu R, Chandran R, Ntokou A, Gallardo-Vara E, Aryal B, Rotllan N, Garcia-Milian R, Hwa J, Kluger Y, Martin K, Fernández-Hernando C, Greif D. The age of bone marrow dictates the clonality of smooth muscle-derived cells in atherosclerotic plaques. Nature Aging 2023, 3: 64-81. PMID: 36743663, PMCID: PMC9894379, DOI: 10.1038/s43587-022-00342-5.Peer-Reviewed Original ResearchConceptsAtherosclerotic plaquesBone marrowSmooth muscle-derived cellsSMC progenitorsAtherosclerotic plaque cellsSmooth muscle cell progenitorsPredominant risk factorCause of deathNovel therapeutic strategiesTNF receptor 1Muscle-derived cellsAged bone marrowAged BMEffect of agePlaque burdenAged miceRisk factorsTumor necrosisTherapeutic strategiesPlaque cellsMyeloid cellsReceptor 1Integrin β3Cell progenitorsAtherosclerosis
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 factorHistone Acetyltransferases p300 and CBP Coordinate Distinct Chromatin Remodeling Programs in Vascular Smooth Muscle Plasticity
Chakraborty R, Ostriker AC, Xie Y, Dave JM, Gamez-Mendez A, Chatterjee P, Abu Y, Valentine J, Lezon-Geyda K, Greif DM, Schulz VP, Gallagher PG, Sessa WC, Hwa J, Martin KA. Histone Acetyltransferases p300 and CBP Coordinate Distinct Chromatin Remodeling Programs in Vascular Smooth Muscle Plasticity. Circulation 2022, 145: 1720-1737. PMID: 35502657, DOI: 10.1161/circulationaha.121.057599.Peer-Reviewed Original ResearchConceptsHistone acetylationContractile genesContractile protein expressionPhenotypic switchingHistone acetyl transferase p300Human intimal hyperplasiaPlatelet-derived growth factor treatmentAcetyl transferase p300Key regulatory mechanismSmooth muscle cell phenotypeP300 expressionP300-dependent acetylationSmooth muscle plasticityDistinct functional interactionsMuscle cell phenotypeProtein expressionIntimal hyperplasiaRole of p300Methylcytosine dioxygenase TET2Chromatin modificationsEpigenetic regulationVSMC phenotypic switchingSpecific histoneCardiovascular diseaseMaster regulatorJAGGED1/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- Dave, JM, Saito, J, Mottola, G, Greif, DM. Invited chapter: Out to the tissues: the arterial side (arteries, arterioles – development, structure, functions, pathologies). In: Z. Gallis. The Vasculome: From Many to One. Philadelphia, PA: Elsevier Inc.; 2022, pp 89-98.Books
Chapter 8 Out to the tissues the arterial side (arteries, arterioles—development, structure, functions, and pathologies)
Dave J, Saito J, Mottola G, Greif D. Chapter 8 Out to the tissues the arterial side (arteries, arterioles—development, structure, functions, and pathologies). 2022, 89-98. DOI: 10.1016/b978-0-12-822546-2.00015-0.Peer-Reviewed Original Research
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 fibrogenesisSNCs meet SMCs in the atherosclerotic plaque
Kabir I, Greif D. SNCs meet SMCs in the atherosclerotic plaque. Nature Aging 2021, 1: 631-633. PMID: 36540165, PMCID: PMC9762735, DOI: 10.1038/s43587-021-00096-6.Commentaries, Editorials and LettersMogamulizumab-Associated Acute Myocarditis in a Patient With T-Cell Lymphoma
Kwan JM, Odanovic N, Arbune A, Higgins A, Henry M, Greif D, Foss F, Baldassarre LA. Mogamulizumab-Associated Acute Myocarditis in a Patient With T-Cell Lymphoma. JACC Case Reports 2021, 3: 1018-1023. PMID: 34317676, PMCID: PMC8311348, DOI: 10.1016/j.jaccas.2021.04.001.Peer-Reviewed Original ResearchTargeting smooth muscle cell phenotypic switching in vascular disease
Chakraborty R, Chatterjee P, Dave JM, Ostriker AC, Greif DM, Rzucidlo EM, Martin KA. Targeting smooth muscle cell phenotypic switching in vascular disease. JVS Vascular Science 2021, 2: 79-94. PMID: 34617061, PMCID: PMC8489222, DOI: 10.1016/j.jvssci.2021.04.001.Peer-Reviewed Original ResearchSingle-cell transcriptomicsVascular smooth muscle cellsVSMC phenotypic modulationPhenotypic plasticityCell transcriptomicsPhenotypic modulationMature vascular smooth muscle cellsSmooth muscle cell phenotypicLineage tracing methodStriking diversityFundamental new insightsMolecular mechanismsFate mappingRemarkable plasticityBromodomain inhibitorsHistone deacetylasePhenotypic switchingPharmacologic inhibitorsGenetic targetingVSMC phenotypicDruggable pathwaysSmooth muscle cellsOligoclonal lesionsTranscriptomicsRecent discoveryMacrophage-derived PDGF-B induces muscularization in murine and human pulmonary hypertension
Ntokou A, Dave JM, Kauffman AC, Sauler M, Ryu C, Hwa J, Herzog EL, Singh I, Saltzman WM, Greif DM. Macrophage-derived PDGF-B induces muscularization in murine and human pulmonary hypertension. JCI Insight 2021, 6: e139067. PMID: 33591958, PMCID: PMC8026182, DOI: 10.1172/jci.insight.139067.Peer-Reviewed Original ResearchConceptsRight ventricle hypertrophyPulmonary hypertensionDistal muscularizationSmooth muscle cellsHypoxia-inducible factor 2APulmonary arterial hypertension patientsLysM-Cre miceArterial hypertension patientsHuman pulmonary hypertensionHypoxia-inducible factor 1aPlatelet-derived growth factorMacrophage-conditioned mediumVentricle hypertrophyHypertension patientsDistal arteriolesMacrophage accumulationFl miceCardiovascular diseaseInterventional strategiesMuscularizationHypoxia exposureExcess macrophagesSMC proliferationLethal diseaseMuscle cellsMacrophage-derived netrin-1 drives adrenergic nerve–associated lung fibrosis
Gao R, Peng X, Perry C, Sun H, Ntokou A, Ryu C, Gomez JL, Reeves BC, Walia A, Kaminski N, Neumark N, Ishikawa G, Black KE, Hariri LP, Moore MW, Gulati M, Homer RJ, Greif DM, Eltzschig HK, Herzog EL. Macrophage-derived netrin-1 drives adrenergic nerve–associated lung fibrosis. Journal Of Clinical Investigation 2021, 131: e136542. PMID: 33393489, PMCID: PMC7773383, DOI: 10.1172/jci136542.Peer-Reviewed Original ResearchConceptsNetrin-1Lung fibrosisCell-specific knockout miceΑ1-adrenoreceptor blockadeIPF lung tissueNeuronal guidance proteinsNetrin-1 expressionExtracellular matrix accumulationAdrenergic processesAdrenoreceptor antagonismAdrenoreceptor blockadeFibrotic histologyInflammatory scarringIPF cohortAdrenergic nervesΑ1-blockersImproved survivalColorectal carcinomaLung tissueKnockout miceCollagen accumulationFibrosisMatrix accumulationMacrophagesGuidance proteins
2020
Specialized Smooth Muscle Cell Progenitors in Pulmonary Hypertension
Saddouk F, Ntokou A, Greif D. Specialized Smooth Muscle Cell Progenitors in Pulmonary Hypertension. 2020, 25-30. DOI: 10.1007/978-981-15-1185-1_4.ChaptersSmooth muscle cellsPulmonary hypertensionNormal lungArteriole smooth muscle cellsPulmonary artery complianceSmooth muscle cell progenitorsStrong independent predictorPlatelet-derived growth factor receptorKruppel-like factor 4Diverse cardiovascular diseasesHypoxia-inducible factorGrowth factor receptorArtery complianceIndependent predictorsTherapeutic optionsIdiopathic formCardiovascular diseaseDependent signaling contributesSignaling contributesHypertensionSMC progenitorsMuscle cellsFactor receptorNon-cell autonomous mannerCell progenitors- Saddouk, FZ, Ntokou, A, Greif, DM. Invited chapter: Specialized smooth muscle cell progenitors in pulmonary hypertension. In: T. Naknishi, H. Baldwin, J. Fineman, and H. Yamagishi, editors. Molecular Mechanism of Congenital Heart Disease and Pulmonary Hypertension. Springer Nature, 2020, pp 25-30.Books
2019
Promoters to Study Vascular Smooth Muscle
Chakraborty R, Saddouk FZ, Carrao AC, Krause DS, Greif DM, Martin KA. Promoters to Study Vascular Smooth Muscle. Arteriosclerosis Thrombosis And Vascular Biology 2019, 39: 603-612. PMID: 30727757, PMCID: PMC6527360, DOI: 10.1161/atvbaha.119.312449.Peer-Reviewed Original ResearchMeSH KeywordsActinsAnimalsCell LineCell LineageCell TransdifferentiationGene Expression RegulationGene Knockout TechniquesGene TargetingHumansMiceMicrofilament ProteinsMuscle ProteinsMuscle, Smooth, VascularMyocytes, Smooth MuscleMyofibroblastsMyosin Heavy ChainsNeovascularization, PathologicNeovascularization, PhysiologicPhenotypePromoter Regions, GeneticRecombinant Fusion ProteinsConceptsSmooth muscle cellsCre driver linesDiversity of phenotypesMuscle cell typesVisceral smooth muscle cellsSMC transdifferentiationActa2 promoterRemarkable plasticityExciting new eraSMC functionCell typesCre linesEmbryonic heartExciting discoveriesPhenotypeMuscle cellsPerivascular adipocytesPromoterVascular smooth muscleNonmuscular cellsExpressionMyeloid cellsCardiovascular phenotypesCellsBlood vessel wall