2024
Endothelial γ-protocadherins inhibit KLF2 and KLF4 to promote atherosclerosis
Joshi D, Coon B, Chakraborty R, Deng H, Yang Z, Babar M, Fernandez-Tussy P, Meredith E, Attanasio J, Joshi N, Traylor J, Orr A, Fernandez-Hernando C, Libreros S, Schwartz M. Endothelial γ-protocadherins inhibit KLF2 and KLF4 to promote atherosclerosis. Nature Cardiovascular Research 2024, 3: 1035-1048. PMID: 39232138, PMCID: PMC11399086, DOI: 10.1038/s44161-024-00522-z.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAtherosclerosisCadherin Related ProteinsCadherinsDisease Models, AnimalEndothelial CellsHuman Umbilical Vein Endothelial CellsHumansKruppel-Like Factor 4Kruppel-Like Transcription FactorsMaleMiceMice, Inbred C57BLMice, KnockoutPlaque, AtheroscleroticReceptors, NotchSignal TransductionConceptsAtherosclerotic cardiovascular diseaseIntracellular domainNotch intracellular domainTranscription factor KLF2Mechanisms of vascular inflammationAnti-inflammatory programVascular endothelial cellsHost defenseCleavage resultsAntibody blockadeGenetic deletionVascular inflammationViral infectionImmune systemEndothelial cellsCardiovascular diseasePromote atherosclerosisBlood flowKLF2KLF4Suppressive signalsEndotheliumMechanistic studies
2022
A mitochondrial contribution to anti-inflammatory shear stress signaling in vascular endothelial cells
Coon BG, Timalsina S, Astone M, Zhuang ZW, Fang J, Han J, Themen J, Chung M, Yang-Klingler YJ, Jain M, Hirschi KK, Yamamato A, Trudeau LE, Santoro M, Schwartz MA. A mitochondrial contribution to anti-inflammatory shear stress signaling in vascular endothelial cells. Journal Of Cell Biology 2022, 221: e202109144. PMID: 35695893, PMCID: PMC9198948, DOI: 10.1083/jcb.202109144.Peer-Reviewed Original ResearchConceptsLaminar shear stressAnti-inflammatory transcription factorHigh laminar shear stressKruppel-like factor 2Vascular endothelial cellsSubsequent mechanistic investigationsArterial lesionsVascular inflammationDisturbed blood flowMyocardial infarctionVascular diseaseVascular remodelingBlood flowKLF2 expressionWhole-genome CRISPREndothelial cellsMajor causeBiomechanical factorsFactor 2Mitochondrial calciumMitochondrial metabolismKLF2InductionMetabolismMitochondrial pathway
2021
Fibronectin‐Mediated Inflammatory Signaling Through Integrin α5 in Vascular Remodeling
Budatha M, Zhang J, Schwartz MA. Fibronectin‐Mediated Inflammatory Signaling Through Integrin α5 in Vascular Remodeling. Journal Of The American Heart Association 2021, 10: e021160. PMID: 34472370, PMCID: PMC8649308, DOI: 10.1161/jaha.121.021160.Peer-Reviewed Original ResearchConceptsTransverse aortic constrictionPathological vascular remodelingVascular remodelingCarotid ligation modelPartial carotid ligation modelAortic constrictionInflammatory activationEndothelial cellsLigation modelArtery wall hypertrophyTransverse aortic constriction (TAC) modelHigh-fat dietIntegrin α5Aortic constriction modelWild-type miceBasement membranePartial carotid ligationVascular endothelial cellsProvisional matrix proteinsAcute atherosclerosisHyperlipidemic ApoEInflammatory markersLigation surgeryWall hypertrophyAcute model
2019
Integrin α5β1 regulates PP2A complex assembly through PDE4D in atherosclerosis
Yun S, Hu R, Schwaemmle ME, Scherer AN, Zhuang Z, Koleske AJ, Pallas DC, Schwartz MA. Integrin α5β1 regulates PP2A complex assembly through PDE4D in atherosclerosis. Journal Of Clinical Investigation 2019, 129: 4863-4874. PMID: 31408443, PMCID: PMC6819111, DOI: 10.1172/jci127692.Peer-Reviewed Original ResearchConceptsPP2A regulatory subunit B55αTranscription factor YAPActive PDEComplex assemblyAdapter rolePDE4D5B55αIntegrin α5EC phenotypeCell functionInflammatory signalingAthero-prone regionsActivationComplexesPP2AInflammatory activationWidespread consequencesDephosphorylationProteomicsVascular remodelingPlaque sizeAtherosclerotic plaque sizeSignalingYAPRegulatesEndothelial TGF-β signalling drives vascular inflammation and atherosclerosis
Chen PY, Qin L, Li G, Wang Z, Dahlman JE, Malagon-Lopez J, Gujja S, Cilfone N, Kauffman K, Sun L, Sun H, Zhang X, Aryal B, Canfran-Duque A, Liu R, Kusters P, Sehgal A, Jiao Y, Anderson D, Gulcher J, Fernandez-Hernando C, Lutgens E, Schwartz M, Pober J, Chittenden T, Tellides G, Simons M. Endothelial TGF-β signalling drives vascular inflammation and atherosclerosis. Nature Metabolism 2019, 1: 912-926. PMID: 31572976, PMCID: PMC6767930, DOI: 10.1038/s42255-019-0102-3.Peer-Reviewed Original ResearchConceptsTGF-β signalingVascular inflammationDisease progressionPlaque growthProgressive vascular diseaseVessel wall inflammationChronic inflammatory responseSpecific therapeutic interventionsAtherosclerotic plaque growthHyperlipidemic micePlaque inflammationWall inflammationProinflammatory effectsVascular diseaseInflammatory responseVascular permeabilityAtherosclerotic plaquesAbnormal shear stressTherapeutic interventionsInflammationEndothelial TGFΒ signalingVessel wallAtherosclerosisLipid retentionCaveolin-1 Regulates Atherogenesis by Attenuating Low-Density Lipoprotein Transcytosis and Vascular Inflammation Independently of Endothelial Nitric Oxide Synthase Activation
Ramírez CM, Zhang X, Bandyopadhyay C, Rotllan N, Sugiyama MG, Aryal B, Liu X, He S, Kraehling JR, Ulrich V, Lin CS, Velazquez H, Lasunción MA, Li G, Suárez Y, Tellides G, Swirski FK, Lee WL, Schwartz MA, Sessa WC, Fernández-Hernando C. Caveolin-1 Regulates Atherogenesis by Attenuating Low-Density Lipoprotein Transcytosis and Vascular Inflammation Independently of Endothelial Nitric Oxide Synthase Activation. Circulation 2019, 140: 225-239. PMID: 31154825, PMCID: PMC6778687, DOI: 10.1161/circulationaha.118.038571.Peer-Reviewed Original ResearchConceptsEndothelial nitric oxide synthaseDiet-induced atherosclerosisNO productionVascular inflammationENOS activationEndothelial nitric oxide synthase activationNitric oxide synthase activationAthero-protective functionsLipid metabolic factorsEndothelial cell inflammationNitric oxide synthaseWild-type miceMice Lacking ExpressionProduction of NOExtracellular matrix remodelingInflammatory primingHyperlipidemic miceInflammatory pathwaysAortic archCell inflammationOxide synthaseMetabolic factorsMouse modelAtherosclerosisInflammation
2018
Inhibiting Integrin α5 Cytoplasmic Domain Signaling Reduces Atherosclerosis and Promotes Arteriogenesis
Budatha M, Zhang J, Zhuang ZW, Yun S, Dahlman JE, Anderson DG, Schwartz MA. Inhibiting Integrin α5 Cytoplasmic Domain Signaling Reduces Atherosclerosis and Promotes Arteriogenesis. Journal Of The American Heart Association 2018, 7: e007501. PMID: 29382667, PMCID: PMC5850249, DOI: 10.1161/jaha.117.007501.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAortaAortic DiseasesAtherosclerosisCyclic Nucleotide Phosphodiesterases, Type 4Disease Models, AnimalExtracellular MatrixFibronectinsFibrosisGenetic Predisposition to DiseaseHindlimbInflammation MediatorsIntegrin alpha2Integrin alpha5IschemiaLeukocytesMaleMatrix MetalloproteinasesMice, Inbred C57BLMice, Knockout, ApoEMuscle, SkeletalNeovascularization, PhysiologicNF-kappa BPhenotypePlaque, AtheroscleroticSignal TransductionVascular RemodelingConceptsEndothelial inflammatory activationAtherosclerotic plaque sizeInflammatory activationPlaque stabilityVascular remodelingEndothelial NF-κB activationSmooth muscle cell contentPlaque sizeFemoral artery ligationMuscle cell contentTreatment of atherosclerosisInflammatory gene expressionPotential therapeutic targetFibrous cap thicknessNF-κB activationSmaller atherosclerotic plaquesArtery ligationAortic rootHindlimb ischemiaCompensatory remodelingAtherosclerotic plaquesTherapeutic targetLeukocyte contentMetalloproteinase expressionEndothelial basement membrane
2016
Interaction between integrin α5 and PDE4D regulates endothelial inflammatory signalling
Yun S, Budatha M, Dahlman JE, Coon BG, Cameron RT, Langer R, Anderson DG, Baillie G, Schwartz MA. Interaction between integrin α5 and PDE4D regulates endothelial inflammatory signalling. Nature Cell Biology 2016, 18: 1043-1053. PMID: 27595237, PMCID: PMC5301150, DOI: 10.1038/ncb3405.Peer-Reviewed Original ResearchConceptsInflammatory signalingIntegrin α5Enhanced phosphodiesterase activityExtracellular matrix remodellingModulates inflammationTherapeutic targetInflammationProstacyclin secretionLipid metabolismEndothelial cellsMatrix remodellingVivo knockdownECM remodellingBasement membraneIntegrin α2Phosphodiesterase activityMolecular mechanismsRemodellingΑ5Direct bindingSignalingCellsFibronectinAtherosclerosisArteryEndothelial fluid shear stress sensing in vascular health and disease
Baeyens N, Bandyopadhyay C, Coon BG, Yun S, Schwartz MA. Endothelial fluid shear stress sensing in vascular health and disease. Journal Of Clinical Investigation 2016, 126: 821-828. PMID: 26928035, PMCID: PMC4767335, DOI: 10.1172/jci83083.Peer-Reviewed Original ResearchConceptsNormal morphogenesisBiochemical signalsGene expressionSame pathwayFluid shear stressCell behaviorSpecialized mechanismsMorphogenesisPathwayPathological conditionsEndothelial cellsVascular physiologyVascular systemBasic mechanismsRecent advancesFlow signalingSignalingMechanismAdult lifePhysiologyExpression
2014
Syndecan 4 is required for endothelial alignment in flow and atheroprotective signaling
Baeyens N, Mulligan-Kehoe MJ, Corti F, Simon DD, Ross TD, Rhodes JM, Wang TZ, Mejean CO, Simons M, Humphrey J, Schwartz MA. Syndecan 4 is required for endothelial alignment in flow and atheroprotective signaling. Proceedings Of The National Academy Of Sciences Of The United States Of America 2014, 111: 17308-17313. PMID: 25404299, PMCID: PMC4260558, DOI: 10.1073/pnas.1413725111.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAtherosclerosisBlotting, WesternCells, CulturedEndothelial CellsFemaleHuman Umbilical Vein Endothelial CellsHumansKruppel-Like Factor 4Kruppel-Like Transcription FactorsMaleMice, Inbred C57BLMice, KnockoutMicroscopy, ConfocalNF-kappa BReverse Transcriptase Polymerase Chain ReactionRNA InterferenceSignal TransductionStress, MechanicalSyndecan-4Vascular Endothelial Growth Factor Receptor-2ConceptsHuman umbilical vein endothelial cellsNF-κBProinflammatory NF-κBAtherosclerotic plaque burdenKruppel-like factor 2Umbilical vein endothelial cellsVEGF receptor 2Appearance of plaquesVein endothelial cellsHypercholesterolemic micePlaque burdenAntiinflammatory pathwayThoracic aortaReceptor 2Endothelial cellsEndothelial alignmentFlow correlatesCausal roleAtherosclerosisFactor 2MiceCyclic stretchLocalization correlatesActivationSyndecan-4Change of Direction in the Biomechanics of Atherosclerosis
Mohamied Y, Rowland EM, Bailey EL, Sherwin SJ, Schwartz MA, Weinberg PD. Change of Direction in the Biomechanics of Atherosclerosis. Annals Of Biomedical Engineering 2014, 43: 16-25. PMID: 25138165, PMCID: PMC4286626, DOI: 10.1007/s10439-014-1095-4.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAortaAtherosclerosisBiomechanical PhenomenaHemorheologyHumansHydrodynamicsMaleRabbitsConceptsLesion prevalenceEndothelial cellsAnti-inflammatory effectsPro-inflammatory effectsRank correlation coefficientAortic branch ostiaLesion locationRabbit aortaSpearman's rank correlation coefficientArterial systemPrevalenceBranch ostiumConfidence intervalsMature rabbitsAtherosclerosisTime-averaged wall shear stressAgeShear metrics
2013
Endothelial Cell Sensing of Flow Direction
Wang C, Baker BM, Chen CS, Schwartz MA. Endothelial Cell Sensing of Flow Direction. Arteriosclerosis Thrombosis And Vascular Biology 2013, 33: 2130-2136. PMID: 23814115, PMCID: PMC3812824, DOI: 10.1161/atvbaha.113.301826.Peer-Reviewed Original ResearchMeSH KeywordsActin CytoskeletonAnimalsAtherosclerosisCattleCell Culture TechniquesCell ShapeCells, CulturedEndothelial CellsEnzyme ActivationHemodynamicsInflammationMechanotransduction, CellularNF-kappa BNitric OxideNitric Oxide Synthase Type IIIOscillometryPhosphorylationProto-Oncogene Proteins c-aktReactive Oxygen SpeciesRegional Blood FlowStress, MechanicalTime FactorsConceptsEndothelial cellsEndothelial nitric oxide synthaseEndothelial nitric oxide synthase pathwayNitric oxide synthase pathwayNitric oxide synthaseOxide synthase pathwayAtherosclerosis-prone regionsInflammatory activationInflammatory effectsOxide synthaseEndothelial cell responsesCell responsesReactive oxygen productionDisturbed flowNitric oxideNuclear factorSimilar effectsActivationCellsSynthase pathwayInability of cellsFlow-dependent cellular mechanotransduction in atherosclerosis
Conway DE, Schwartz MA. Flow-dependent cellular mechanotransduction in atherosclerosis. Journal Of Cell Science 2013, 126: 5101-5109. PMID: 24190880, PMCID: PMC3828588, DOI: 10.1242/jcs.138313.Peer-Reviewed Original Research
2012
The role of p21-activated kinase in the initiation of atherosclerosis
Jhaveri K, Debnath P, Chernoff J, Sanders J, Schwartz M. The role of p21-activated kinase in the initiation of atherosclerosis. BMC Cardiovascular Disorders 2012, 12: 55. PMID: 22824149, PMCID: PMC3489605, DOI: 10.1186/1471-2261-12-55.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAorta, ThoracicAortic DiseasesAtherosclerosisBiomechanical PhenomenaCells, CulturedDisease Models, AnimalEndothelial CellsFibronectinsGalectin 3ImmunohistochemistryInflammation MediatorsIntercellular Adhesion Molecule-1MaleMiceMice, Inbred C57BLMice, KnockoutP21-Activated KinasesRegional Blood FlowTranscription Factor RelBVascular Cell Adhesion Molecule-1ConceptsLesser curvatureNF-κB subunitsInflammatory activationEndothelial cellsAtherosclerosis-prone sitesPro-inflammatory functionsInflammatory marker expressionNormal chow dietArch of aortaInitiation of atherosclerosisInflammatory markersOverall inflammationChow dietInflammatory pathwaysYoung miceAtherosclerosis-susceptible regionsConclusionThese dataICAM-1VCAM-1NF-κBRelA NF-κB subunitMarker expressionLow levelsFibronectin depositionInflammationA novel in vitro flow system for changing flow direction on endothelial cells
Wang C, Lu H, Schwartz MA. A novel in vitro flow system for changing flow direction on endothelial cells. Journal Of Biomechanics 2012, 45: 1212-1218. PMID: 22386042, PMCID: PMC3327813, DOI: 10.1016/j.jbiomech.2012.01.045.Peer-Reviewed Original Research
2010
Atheroprone Hemodynamics Regulate Fibronectin Deposition to Create Positive Feedback That Sustains Endothelial Inflammation
Feaver RE, Gelfand BD, Wang C, Schwartz MA, Blackman BR. Atheroprone Hemodynamics Regulate Fibronectin Deposition to Create Positive Feedback That Sustains Endothelial Inflammation. Circulation Research 2010, 106: 1703-1711. PMID: 20378855, PMCID: PMC2891748, DOI: 10.1161/circresaha.109.216283.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAortic DiseasesApolipoproteins EAtherosclerosisCells, CulturedDisease Models, AnimalEndothelium, VascularFeedback, PhysiologicalFibronectinsHemodynamicsHumansInflammationMechanotransduction, CellularMiceMice, Inbred C57BLMice, KnockoutNF-kappa BPlatelet Endothelial Cell Adhesion Molecule-1Pulsatile FlowRegional Blood FlowRNA InterferenceStress, MechanicalTime FactorsTransfectionUp-RegulationConceptsFN depositionAtheroprone flowPECAM-1FN expressionTranscription factor NF-kappaB.Platelet endothelial cell adhesion moleculeNF-kappaB activationNF-kappaB activityAtheroprone hemodynamicsHuman endothelial cellsEndothelial inflammationProinflammatory phenotypeAortic archInduction of fibronectinCarotid arteryCell adhesion moleculeExogenous fibronectinInflammatory signalingFN accumulationNF-kappaBSustained increaseNF-kappaB.Nuclear factorTransient increaseEndothelial cells
2009
The Subendothelial Extracellular Matrix Modulates JNK Activation by Flow
Hahn C, Orr AW, Sanders JM, Jhaveri KA, Schwartz MA. The Subendothelial Extracellular Matrix Modulates JNK Activation by Flow. Circulation Research 2009, 104: 995-1003. PMID: 19286608, PMCID: PMC2702158, DOI: 10.1161/circresaha.108.186486.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApolipoproteins EAtherosclerosisBasement MembraneCattleCell Culture TechniquesCells, CulturedCollagenDisease Models, AnimalEndothelial CellsEnzyme ActivationExtracellular MatrixFibronectinsHemorheologyInflammationIntegrinsJNK Mitogen-Activated Protein KinasesMiceMice, Inbred C57BLMice, KnockoutMitogen-Activated Protein Kinase KinasesOscillometryP21-Activated KinasesPhosphorylationRegional Blood FlowStress, MechanicalMechanotransduction in vascular physiology and atherogenesis
Hahn C, Schwartz MA. Mechanotransduction in vascular physiology and atherogenesis. Nature Reviews Molecular Cell Biology 2009, 10: 53-62. PMID: 19197332, PMCID: PMC2719300, DOI: 10.1038/nrm2596.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAtherosclerosisBlood Flow VelocityBlood VesselsHumansMechanotransduction, CellularRisk FactorsConceptsImportant regulatory factorEndothelial extracellular matrixBiochemical signalsGene expressionBlood pressureRegulatory factorsCellular responsesRegions of arteriesFluid shear stressBlood flowExtracellular matrixPhysiological responsesProgression of atherosclerosisSystemic risk factorsNormal physiological responseMechanical forcesChronic inflammationPhysiologyVascular physiologyRisk factorsHigh cholesterolVascular endotheliumAtherosclerosisBlood vesselsCells
2008
The Role of Cellular Adaptation to Mechanical Forces in Atherosclerosis
Hahn C, Schwartz MA. The Role of Cellular Adaptation to Mechanical Forces in Atherosclerosis. Arteriosclerosis Thrombosis And Vascular Biology 2008, 28: 2101-2107. PMID: 18787190, PMCID: PMC2737679, DOI: 10.1161/atvbaha.108.165951.Peer-Reviewed Original ResearchConceptsDisease progressionChronic inflammatory diseaseSystemic risk factorsInflammatory pathwaysInflammatory diseasesRisk factorsRegions of arteriesPlaque formationAtherosclerosisProgressionCellular adaptationPotential mechanosensorsAdaptive responseCellular responsesGene expressionHyperlipidemiaSubsequent changesSmokingDiabetesArteryPathwayDiseaseVasculatureResponseEndothelial Cell PECAM-1 Promotes Atherosclerotic Lesions in Areas of Disturbed Flow in ApoE-Deficient Mice
Harry BL, Sanders JM, Feaver RE, Lansey M, Deem TL, Zarbock A, Bruce AC, Pryor AW, Gelfand BD, Blackman BR, Schwartz MA, Ley K. Endothelial Cell PECAM-1 Promotes Atherosclerotic Lesions in Areas of Disturbed Flow in ApoE-Deficient Mice. Arteriosclerosis Thrombosis And Vascular Biology 2008, 28: 2003-2008. PMID: 18688018, PMCID: PMC2651147, DOI: 10.1161/atvbaha.108.164707.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAorta, AbdominalAorta, ThoracicApolipoproteins EAtherosclerosisBone Marrow CellsBone Marrow TransplantationCells, CulturedDietary FatsDisease Models, AnimalDisease ProgressionEndothelial CellsHumansMacrophagesMiceMice, Inbred C57BLMice, KnockoutNF-kappa BPlatelet Endothelial Cell Adhesion Molecule-1Regional Blood FlowRNA InterferenceRNA, Small InterferingStress, MechanicalVascular Cell Adhesion Molecule-1ConceptsEndothelial PECAM-1PECAM-1Aortic archAbdominal aortaNF-kappaBVascular cell adhesion molecule-1 expressionCell adhesion molecule-1 expressionAdhesion molecule-1 expressionCell adhesion molecule-1ApoE-deficient miceAtherosclerotic lesion sizeBone marrow transplantationAtherosclerotic lesion formationMolecule-1 expressionVCAM-1 expressionAdhesion molecule-1Endothelial cell adhesion molecule-1NF-kappaB activityNuclear NF-kappaBDisturbed flowMarrow transplantationMacrophage infiltrationLesser curvatureWestern dietDeficient mice