2024
Dysregulated cellular metabolism in atherosclerosis: mediators and therapeutic opportunities
Stroope C, Nettersheim F, Coon B, Finney A, Schwartz M, Ley K, Rom O, Yurdagul A. Dysregulated cellular metabolism in atherosclerosis: mediators and therapeutic opportunities. Nature Metabolism 2024, 6: 617-638. PMID: 38532071, PMCID: PMC11055680, DOI: 10.1038/s42255-024-01015-w.Peer-Reviewed Original ResearchDysregulated cellular metabolismAtherosclerotic cardiovascular diseaseLesional cellsAtherosclerosis progressionCardiovascular diseaseDysregulation of cellular metabolismVascular smooth muscle cellsProgression of atherosclerotic cardiovascular diseaseSmooth muscle cellsCellular metabolismT cellsMetabolic alterationsMuscle cellsMetabolic dysregulationCardiovascular therapeuticsTherapeutic opportunitiesEndothelial cellsTherapeutic targetMetabolic cross-talkAtherosclerosisCellsDiseaseDysregulationCross-talkMetabolism
2021
MEKK3–TGFβ crosstalk regulates inward arterial remodeling
Deng H, Xu Y, Hu X, Zhuang ZW, Chang Y, Wang Y, Ntokou A, Schwartz MA, Su B, Simons M. MEKK3–TGFβ crosstalk regulates inward arterial remodeling. Proceedings Of The National Academy Of Sciences Of The United States Of America 2021, 118: e2112625118. PMID: 34911761, PMCID: PMC8713777, DOI: 10.1073/pnas.2112625118.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsGene DeletionGene Expression RegulationGenotypeHindlimbHuman Umbilical Vein Endothelial CellsHumansHypertension, PulmonaryIschemiaMAP Kinase Kinase Kinase 1MAP Kinase Kinase Kinase 3MiceReceptors, Transforming Growth Factor betaSelective Estrogen Receptor ModulatorsSignal TransductionTamoxifenTransforming Growth Factor betaVascular RemodelingConceptsArterial remodelingSuch common diseasesEndothelial-specific deletionActivation of TGFβArtery diseaseHyperlipidemic miceSpontaneous hypertensionInward remodelingAccelerated progressionArterial diameterVascular remodelingPathogenic importanceAdult miceKnockout miceVascular circuitPathologic conditionsCommon diseaseMAPK ERK1/2MiceRemodelingHypertensionAtherosclerosisControl of proliferationDiseaseProgression
2020
Endothelial-to-Mesenchymal Transition, Vascular Inflammation, and Atherosclerosis
Chen PY, Schwartz MA, Simons M. Endothelial-to-Mesenchymal Transition, Vascular Inflammation, and Atherosclerosis. Frontiers In Cardiovascular Medicine 2020, 7: 53. PMID: 32478094, PMCID: PMC7232582, DOI: 10.3389/fcvm.2020.00053.Peer-Reviewed Original ResearchVascular inflammationMesenchymal transitionBiology of atherosclerosisPotential new therapeutic targetChronic progressive diseaseNew therapeutic targetsSelective inflammatory mediatorsProgressive diseaseInflammatory mediatorsAtherosclerotic plaquesBlood flowTherapeutic targetPlaque growthInflammationAtherosclerosisMultiple attemptsDiseaseMolecular mechanismsEndMTPlaques
2019
Endothelial 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 modelAtherosclerosisInflammationARHGAP18: A Flow‐Responsive Gene That Regulates Endothelial Cell Alignment and Protects Against Atherosclerosis
Lay AJ, Coleman PR, Formaz‐Preston A, Ting KK, Roediger B, Weninger W, Schwartz MA, Vadas MA, Gamble JR. ARHGAP18: A Flow‐Responsive Gene That Regulates Endothelial Cell Alignment and Protects Against Atherosclerosis. Journal Of The American Heart Association 2019, 8: e010057. PMID: 30630384, PMCID: PMC6497359, DOI: 10.1161/jaha.118.010057.Peer-Reviewed Original ResearchConceptsApolipoprotein EHigh-fat diet-induced modelIntercellular adhesion molecule-1Endothelial nitric oxide synthaseHigh-fat dietDevelopment of atherosclerosisNitric oxide synthaseDiet-induced modelAdhesion molecule-1Double mutant miceAortic diseaseAtherosclerosis developmentInflammatory phenotypeOxide synthaseMolecule-1AtherosclerosisEarly onsetProtective genesMiceFlow-responsive genesAtheroprotective regionsEndothelial cell alignmentAdaptive responseAnalysis of ECEC ability
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 bindingSignalingCellsFibronectinAtherosclerosisArtery
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 ResearchConceptsLesion 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
Flow-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
2009
Mechanotransduction 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 ResearchConceptsImportant 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 changesSmokingDiabetesArteryPathwayDiseaseVasculatureResponse
2006
A mechanosensory complex that mediates the endothelial cell response to fluid shear stress
Tzima E, Irani‐Tehrani M, Kiosses W, Dejana E, Schultz D, Engelhardt B, Cao G, DeLisser H, Schwartz M. A mechanosensory complex that mediates the endothelial cell response to fluid shear stress. The FASEB Journal 2006, 20: a1378-a1378. DOI: 10.1096/fasebj.20.5.a1378-c.Peer-Reviewed Original ResearchPECAM-1-null miceDownstream inflammatory genesPECAM-1VE-cadherinDevelopment of atherosclerosisICAM-1 expressionNF-kB activationInitiation of atherosclerosisBlood pressureVascular remodelingHigh-affinity stateInflammatory genesNF-κBCell responsesEndothelial cell responsesNull miceMechanosensory complexIntegrin activationAffinity stateAtherosclerosisVEGFR2Heterologous cellsPathway upstreamActivationSrc family kinases
2005
The subendothelial extracellular matrix modulates NF-κB activation by flow
Orr AW, Sanders JM, Bevard M, Coleman E, Sarembock IJ, Schwartz MA. The subendothelial extracellular matrix modulates NF-κB activation by flow. Journal Of Cell Biology 2005, 169: 191-202. PMID: 15809308, PMCID: PMC2171897, DOI: 10.1083/jcb.200410073.Peer-Reviewed Original ResearchConceptsNF-kappaB activationSubendothelial extracellular matrixAtherosclerosis-prone sitesEarly monocyte recruitmentSigns of atherosclerosisFatty streak formationNovel therapeutic strategiesNF-κB activationSuppress NF-kappaB activationExtracellular matrixMonocyte recruitmentICAM-1VCAM-1Plaque formTherapeutic strategiesE-selectinP38-dependent pathwayNF-kappaBEndothelial cellsAtherosclerosisP38 activationNew integrinActivationStreak formationIntegrin alpha2beta1