2024
Abstract 1147: Crosstalk Between Alk5 And Mtorc1 Signaling Promotes VSMC Differentiation And The Therapeutic Effect Of Rapamycin
Chakraborty R, Chatterjee P, Dave J, Obrien B, Joshi D, Schulz V, Greif D, Hwa J, Gallagher P, Martin K. Abstract 1147: Crosstalk Between Alk5 And Mtorc1 Signaling Promotes VSMC Differentiation And The Therapeutic Effect Of Rapamycin. Arteriosclerosis Thrombosis And Vascular Biology 2024, 44: a1147-a1147. DOI: 10.1161/atvb.44.suppl_1.1147.Peer-Reviewed Original ResearchVascular smooth muscle cellsTherapeutic effect of rapamycinEffects of rapamycinVSMC differentiationContractile genesConsistent with in vitro findingsRapamycin treatmentCarotid artery injuryHuman coronary artery SMCsVascular smooth muscle cell differentiationIntimal hyperplasiaSmooth muscle cellsCoronary artery SMCsMTORC1 inhibitor rapamycinPhosphorylation of Smad2/3Inhibition of ALK5Smad-binding elementSmad transcription factorsALK5 activityArterial injuryArtery SMCsKnockout miceInhibition of mTORC1Vascular smooth muscle cell plasticityMuscle cellsAbstract 129: Hypercholesterolemia-induced Lxr Signaling In Smc Contributes To Atherosclerotic Lesion Remodeling And Regulates Vascular And Visceral Smc Function
Zhang H, Biwer L, de Urturi D, Fernandez-Tussy P, Jovin D, Huang Y, Zhang X, Esplugues E, Greif D, Suarez Y, Fernandez-Hernando C. Abstract 129: Hypercholesterolemia-induced Lxr Signaling In Smc Contributes To Atherosclerotic Lesion Remodeling And Regulates Vascular And Visceral Smc Function. Arteriosclerosis Thrombosis And Vascular Biology 2024, 44: a129-a129. DOI: 10.1161/atvb.44.suppl_1.129.Peer-Reviewed Original ResearchLiver X receptorTranscription factorsVascular smooth muscle cellsRegulation of lipid metabolismLXR signalingB geneScRNA-seqFate decisionsSignaling eventsSMC functionGene expressionActivation of liver X receptorCell statesLesion remodelingCharacterized miceLipid metabolismLineage tracingPhenotypic switchingX receptorReduced fibrous cap thicknessTranscriptionFeatures of plaque instabilitySmooth muscle cellsLipid absorptionProgression of atherosclerosisEndothelial 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
2021
Targeting 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 cells
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
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
2018
Integrin beta3 regulates clonality and fate of smooth muscle-derived atherosclerotic plaque cells
Misra A, Feng Z, Chandran RR, Kabir I, Rotllan N, Aryal B, Sheikh AQ, Ding L, Qin L, Fernández-Hernando C, Tellides G, Greif DM. Integrin beta3 regulates clonality and fate of smooth muscle-derived atherosclerotic plaque cells. Nature Communications 2018, 9: 2073. PMID: 29802249, PMCID: PMC5970166, DOI: 10.1038/s41467-018-04447-7.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAortaAtherosclerosisBone Marrow TransplantationCell MovementCell ProliferationCell TransdifferentiationCells, CulturedCholesterolDisease Models, AnimalFemaleHumansIntegrin beta3MacrophagesMaleMiceMice, Inbred C57BLMice, Knockout, ApoEMuscle, Smooth, VascularMyocytes, Smooth MusclePlaque, AtheroscleroticConceptsSmooth muscle cellsPre-existing smooth muscle cellsAtherosclerotic plaquesPlaque cellsToll-like receptor 4 expressionSmooth muscle-derived cellsBone marrow-derived cellsSingle smooth muscle cellsAtherosclerotic plaque cellsReceptor 4 expressionMarrow-derived cellsBone marrow resultsMuscle-derived cellsIntegrin β3 levelsMacrophage-like phenotypeCD36 levelsMarrow resultsSMC proliferationPlaque coresSMC progenitorsMuscle cellsIntegrin β3AtherogenesisPlaquesIntegrin beta3
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 architectureCells
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
2015
Smooth muscle cell progenitors are primed to muscularize in pulmonary hypertension
Sheikh AQ, Misra A, Rosas IO, Adams RH, Greif DM. Smooth muscle cell progenitors are primed to muscularize in pulmonary hypertension. Science Translational Medicine 2015, 7: 308ra159. PMID: 26446956, PMCID: PMC4629985, DOI: 10.1126/scitranslmed.aaa9712.Peer-Reviewed Original ResearchConceptsSmooth muscle cellsKruppel-like factor 4Pulmonary hypertensionSmooth muscleHypoxia-induced pulmonary hypertensionPathogenesis of PHPulmonary artery blood pressureSMC progenitorsArteriole smooth muscleArtery blood pressureSmooth muscle cell progenitorsCardiovascular disease pathogenesisPlatelet-derived growth factor receptorHypoxia-induced expressionGrowth factor receptorPH patientsBlood pressurePulmonary arteriolesVascular disordersTherapeutic strategiesDisease pathogenesisKLF4 levelsKLF4 expressionDistal extensionMuscle cells
2014
Recapitulation of Developing Artery Muscularization in Pulmonary Hypertension
Sheikh AQ, Lighthouse JK, Greif DM. Recapitulation of Developing Artery Muscularization in Pulmonary Hypertension. Cell Reports 2014, 6: 809-817. PMID: 24582963, PMCID: PMC4015349, DOI: 10.1016/j.celrep.2014.01.042.Peer-Reviewed Original ResearchConceptsPulmonary artery hypertensionArtery hypertensionArteriole smooth muscle cellsSmooth muscle accumulationPulmonary artery complianceModest clinical benefitStrong independent predictorMuscle cell dedifferentiationSmooth muscle cellsPulmonary hypertensionArtery complianceIndependent predictorsClinical benefitPulmonary vasculatureDistal migrationVascular disordersAlveolar myofibroblastsSmooth muscleHypertensionMuscle accumulationMuscularizationMuscle cellsCell dedifferentiationPoor understandingAtherosclerosis
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