2024
Controversy in mechanotransduction: the role of endothelial cell-cell junctions in fluid shear stress sensing.
X S, Aitken C, Mehta V, Tardajos-Ayllon B, Serbanovic-Canic J, Zhu J, Miao B, Tzima E, Evans P, Fang Y, Schwartz M. Controversy in mechanotransduction: the role of endothelial cell-cell junctions in fluid shear stress sensing. Journal Of Cell Science 2024 PMID: 39143856, DOI: 10.1242/jcs.262348.Peer-Reviewed Original ResearchShear stress sensingFluid shear stressFluid flowCell-cell contactShear stressCell-cell adhesionStress sensingCell-cell junctionsEndothelial cell-cell junctionsEC alignmentRegulates vascular developmentAdhesion receptorsCell typesEndothelial cellsFlowSingle cellsVascular developmentShearAdhesionContactA KLF2-BMPER-Smad1/5 checkpoint regulates high fluid shear stress-mediated artery remodeling
Deng H, Zhang J, Wang Y, Joshi D, Pi X, De Val S, Schwartz M. A KLF2-BMPER-Smad1/5 checkpoint regulates high fluid shear stress-mediated artery remodeling. Nature Cardiovascular Research 2024, 3: 785-798. DOI: 10.1038/s44161-024-00496-y.Peer-Reviewed Original ResearchFluid shear stressVascular remodelingOutward remodelingBone morphogenetic proteinShear stressMouse models of type 1Ischemic diseasesModels of type 1BMP-binding endothelial regulatorBlood flow recoveryType 2 diabetesPhysiological fluid shear stressPotential therapeutic approachBlocking antibodiesMouse modelSmad1/5 activationArterial remodelingTherapeutic approachesType 1Akt activationBlood flowEndothelial regulationSmad1/5Flow recoveryMorphogenetic proteins
2023
SMAD4 maintains the fluid shear stress set point to protect against arterial-venous malformations
Banerjee K, Lin Y, Gahn J, Cordero J, Gupta P, Mohamed I, Graupera M, Dobreva G, Schwartz M, Ola R. SMAD4 maintains the fluid shear stress set point to protect against arterial-venous malformations. Journal Of Clinical Investigation 2023, 133: e168352. PMID: 37490341, PMCID: PMC10503796, DOI: 10.1172/jci168352.Peer-Reviewed Original ResearchConceptsActivin-like kinase 1Fluid shear stressSMAD family member 4Arterial identityCyclin-dependent kinase inhibitors Cdkn2aVascular network formsEndothelial cellsVascular stabilitySensitivity of ECsBMP signalsPI3K/AktFamily member 4Downstream effectorsProtein 9Kinase 1Vascular developmentBone morphogenic protein 9Mechanism of synergyMorphological responsesSMAD4 deletionEC proliferationMember 4
2022
High Fluid Shear Stress Inhibits Cytokine‐Driven Smad2/3 Activation in Vascular Endothelial Cells
Deng H, Schwartz MA. High Fluid Shear Stress Inhibits Cytokine‐Driven Smad2/3 Activation in Vascular Endothelial Cells. Journal Of The American Heart Association 2022, 11: e025337. PMID: 35861829, PMCID: PMC9707828, DOI: 10.1161/jaha.121.025337.Peer-Reviewed Original ResearchConceptsInflammatory cytokinesSmad2/3 activationEndothelial cellsNuclear translocationInflammatory cytokine treatmentGrowth factor betaVascular endothelial cellsQuantitative polymerase chain reactionSmad2/3 nuclear translocationTarget gene expressionBackground AtherosclerosisInflammatory mediatorsInflammatory pathwaysPolymerase chain reactionResult of inhibitionCytokine treatmentInhibits CytokineFactor betaMesenchymal transitionHigh fluid shear stressCytokinesEndMTGene expressionLaminar fluid shear stressFluid shear stress
2021
Activation of Smad2/3 signaling by low fluid shear stress mediates artery inward remodeling
Deng H, Min E, Baeyens N, Coon BG, Hu R, Zhuang ZW, Chen M, Huang B, Afolabi T, Zarkada G, Acheampong A, McEntee K, Eichmann A, Liu F, Su B, Simons M, Schwartz MA. Activation of Smad2/3 signaling by low fluid shear stress mediates artery inward remodeling. Proceedings Of The National Academy Of Sciences Of The United States Of America 2021, 118: e2105339118. PMID: 34504019, PMCID: PMC8449390, DOI: 10.1073/pnas.2105339118.Peer-Reviewed Original ResearchConceptsLow fluid shear stressFluid shear stressNuclear translocationSmad linker regionTransmembrane protein Neuropilin-1Target gene expressionCyclin-dependent kinasesBone morphogenetic proteinEC-specific deletionSmad2/3 nuclear translocationNuclear localizationHigh fluid shear stressLinker regionMorphogenetic proteinsGene expressionRegulatory mechanismsActivation of Smad2/3Receptor ALK5Smad2/3 phosphorylationTranslocationCell sensingEndothelial cell (EC) sensingPhosphorylationALK5Smad2/3Early events in endothelial flow sensing
Tanaka K, Joshi D, Timalsina S, Schwartz MA. Early events in endothelial flow sensing. Cytoskeleton 2021, 78: 217-231. PMID: 33543538, DOI: 10.1002/cm.21652.Peer-Reviewed Original ResearchConceptsFluid shear stressLymphatic endothelial cellsEndothelial cellsCytoskeletal pathwaysVascular morphogenesisBiochemical signalsGene expressionEC phenotypeLymphatic fluid flowEarly eventsPhysiologyImmediate mechanismPrimary mechanismRecent advancesMorphogenesisMechanotransductionSignalingPhenotypePathwayMechanismExpressionFlow sensingCellsImportant questions
2017
Shear-induced Notch-Cx37-p27 axis arrests endothelial cell cycle to enable arterial specification
Fang JS, Coon BG, Gillis N, Chen Z, Qiu J, Chittenden TW, Burt JM, Schwartz MA, Hirschi KK. Shear-induced Notch-Cx37-p27 axis arrests endothelial cell cycle to enable arterial specification. Nature Communications 2017, 8: 2149. PMID: 29247167, PMCID: PMC5732288, DOI: 10.1038/s41467-017-01742-7.Peer-Reviewed Original ResearchConceptsEndothelial cell cycle arrestArterial gene expressionCell cycle arrestArterial specificationGene expressionCycle arrestArterial-venous specificationCell cycle inhibitor CDKN1BEndothelial cell cycleCell cycle inhibitionEmbryonic developmentBlood vessel formationP27 axisFunctional vascular networkCell cycleGrowth controlSpecialized phenotypeFluid shear stressCycle inhibitionVessel formationGrowth inhibitionTissue repairMechanochemical pathwayEndothelial cellsVascular regenerationVE-Cadherin Phosphorylation Regulates Endothelial Fluid Shear Stress Responses through the Polarity Protein LGN
Conway DE, Coon BG, Budatha M, Arsenovic PT, Orsenigo F, Wessel F, Zhang J, Zhuang Z, Dejana E, Vestweber D, Schwartz MA. VE-Cadherin Phosphorylation Regulates Endothelial Fluid Shear Stress Responses through the Polarity Protein LGN. Current Biology 2017, 27: 2219-2225.e5. PMID: 28712573, PMCID: PMC5667920, DOI: 10.1016/j.cub.2017.06.020.Peer-Reviewed Original ResearchConceptsSrc family kinasesProtein LGNCytoplasmic tyrosinesVE-cadherinVascular endothelial growth factor receptorVE-cadherin functionJunctional complexesRespective cytoplasmic domainsBlood vessel developmentVE-cadherin phosphorylationTransduce forcesTransduce signalsCytoplasmic domainFamily kinasesBlood vessel remodelingGrowth factor receptorVEGFR activationPECAM-1Stress responseComplex consistingFluid shear stressVessel developmentFlow-dependent vascular remodelingSpecific poolPhosphorylation
2016
Syndecan 4 controls lymphatic vasculature remodeling during mouse embryonic development
Wang Y, Baeyens N, Corti F, Tanaka K, Fang JS, Zhang J, Jin Y, Coon B, Hirschi KK, Schwartz MA, Simons M. Syndecan 4 controls lymphatic vasculature remodeling during mouse embryonic development. Development 2016, 143: 4441-4451. PMID: 27789626, PMCID: PMC5201046, DOI: 10.1242/dev.140129.Peer-Reviewed Original ResearchConceptsLymphatic endothelial cellsPlanar cell polarity protein Vangl2Lymphatic vessel remodelingMouse embryonic developmentHuman lymphatic endothelial cellsVangl2 overexpressionVangl2 expressionEmbryonic developmentValve morphogenesisEndothelial cellsVasculature developmentSyndecan-4Lymphatic vasculatureFluid shear stressSDC4Double knockout miceMice resultsHigh expressionVessel remodelingLymphatic vesselsExpressionVangl2RemodelingCellsMorphogenesisEndothelial 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 lifePhysiologyExpressionBiomechanics of vascular mechanosensation and remodeling
Baeyens N, Schwartz MA. Biomechanics of vascular mechanosensation and remodeling. Molecular Biology Of The Cell 2016, 27: 7-11. PMID: 26715421, PMCID: PMC4694763, DOI: 10.1091/mbc.e14-11-1522.Peer-Reviewed Original Research
2015
Intramembrane binding of VE-cadherin to VEGFR2 and VEGFR3 assembles the endothelial mechanosensory complex
Coon BG, Baeyens N, Han J, Budatha M, Ross TD, Fang JS, Yun S, Thomas JL, Schwartz MA. Intramembrane binding of VE-cadherin to VEGFR2 and VEGFR3 assembles the endothelial mechanosensory complex. Journal Of Cell Biology 2015, 208: 975-986. PMID: 25800053, PMCID: PMC4384728, DOI: 10.1083/jcb.201408103.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigens, CDCadherinsCell MovementCells, CulturedEndothelium, VascularHEK293 CellsHuman Umbilical Vein Endothelial CellsHumansMechanotransduction, CellularMiceMice, Inbred C57BLNeovascularization, PhysiologicPlaque, AtheroscleroticPlatelet Endothelial Cell Adhesion Molecule-1Protein Structure, TertiaryRNA InterferenceRNA, Small InterferingStress, MechanicalStress, PhysiologicalVascular Endothelial Growth Factor Receptor-2Vascular Endothelial Growth Factor Receptor-3
2013
Fluid Shear Stress on Endothelial Cells Modulates Mechanical Tension across VE-Cadherin and PECAM-1
Conway DE, Breckenridge MT, Hinde E, Gratton E, Chen CS, Schwartz MA. Fluid Shear Stress on Endothelial Cells Modulates Mechanical Tension across VE-Cadherin and PECAM-1. Current Biology 2013, 23: 1024-1030. PMID: 23684974, PMCID: PMC3676707, DOI: 10.1016/j.cub.2013.04.049.Peer-Reviewed Original ResearchConceptsFluid shear stressVE-cadherinCell-cell junctionsPECAM-1Junctional tensionCytoskeletal remodelingVascular morphogenesisGene expressionComplex consistingCells triggersFlow-dependent vascular remodelingIon channelsFRET measurementsEndothelial cells triggersMechanical tensionNormal vascular functionTension sensorDetectable tensionEC responseStatic cultureJunctional receptorsRemodelingCytoskeletonMorphogenesisVascular remodeling
2012
Lessons from the endothelial junctional mechanosensory complex
Conway D, Schwartz MA. Lessons from the endothelial junctional mechanosensory complex. F1000 Biology Reports 2012, 4: 1. PMID: 22238515, PMCID: PMC3251317, DOI: 10.3410/b4-1.Peer-Reviewed Original Research
2009
Focal adhesion kinase modulates activation of NF-κB by flow in endothelial cells
Petzold T, Orr AW, Hahn C, Jhaveri KA, Parsons JT, Schwartz MA. Focal adhesion kinase modulates activation of NF-κB by flow in endothelial cells. American Journal Of Physiology - Cell Physiology 2009, 297: c814-c822. PMID: 19587216, PMCID: PMC2770750, DOI: 10.1152/ajpcell.00226.2009.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell NucleusCells, CulturedEndothelial CellsEndothelium, VascularFocal Adhesion Protein-Tyrosine KinasesHydrogen PeroxideI-kappa B KinaseIntegrinsIntercellular Adhesion Molecule-1MiceNF-kappa BPhosphorylationProtein TransportRac GTP-Binding ProteinsReactive Oxygen SpeciesSignal TransductionStress, MechanicalTranscription Factor RelATumor Necrosis Factor-alphaConceptsFocal adhesion kinaseAdhesion kinaseNF-kappaBRac activationTranscriptional activityDependent genesEndothelial cellsIntegrin activationP65 NF-kappaB subunitDegradation of IkappaBReactive oxygen productionFluid shear stressNF-kappaB subunitsSerine 536Phosphorylation of p65Novel mechanismNF-kappaB activationKinaseNF-kappaB phosphorylationPhosphorylationActivationNF-κBOxygen productionHydrogen peroxideCellsThe 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 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
2003
Rho-ROCK-LIMK-Cofilin Pathway Regulates Shear Stress Activation of Sterol Regulatory Element Binding Proteins
Lin T, Zeng L, Liu Y, DeFea K, Schwartz MA, Chien S, Shyy J. Rho-ROCK-LIMK-Cofilin Pathway Regulates Shear Stress Activation of Sterol Regulatory Element Binding Proteins. Circulation Research 2003, 92: 1296-1304. PMID: 12775580, DOI: 10.1161/01.res.0000078780.65824.8b.Peer-Reviewed Original ResearchMeSH KeywordsActin Depolymerizing FactorsActinsAnimalsCattleCCAAT-Enhancer-Binding ProteinsCell AdhesionCells, CulturedCHO CellsCricetinaeDNA-Binding ProteinsEndothelium, VascularHumansIntracellular Signaling Peptides and ProteinsLim KinasesLuciferasesMembrane ProteinsMicrofilament ProteinsMicroscopy, FluorescenceMutationPlasmidsProtein KinasesProtein Serine-Threonine KinasesProtein TransportProteinsRho GTP-Binding ProteinsRho-Associated KinasesSignal TransductionSterol Regulatory Element Binding Protein 1Sterol Regulatory Element Binding Protein 2Stress, MechanicalTranscription FactorsTransfectionConceptsSterol regulatory element-binding proteinLIMK-cofilin pathwayRegulatory element-binding proteinLIM kinaseElement-binding proteinRho-ROCKBinding proteinFluid shear stressSREBP cleavage-activating proteinSignal transduction pathwaysSmall GTPase RhoStress activationShear stress activationGolgi transportS2P proteasesTransduction pathwaysNegative mutantGTPase RhoSREBP activationIntegrin activationEndoplasmic reticulumEndothelial cell functionVascular endothelial cellsCaspase-3ProteinLocalized Cdc42 Activation, Detected Using a Novel Assay, Mediates Microtubule Organizing Center Positioning in Endothelial Cells in Response to Fluid Shear Stress*
Tzima E, Kiosses WB, del Pozo MA, Schwartz MA. Localized Cdc42 Activation, Detected Using a Novel Assay, Mediates Microtubule Organizing Center Positioning in Endothelial Cells in Response to Fluid Shear Stress*. Journal Of Biological Chemistry 2003, 278: 31020-31023. PMID: 12754216, DOI: 10.1074/jbc.m301179200.Peer-Reviewed Original ResearchConceptsMicrotubule organizing centerCdc42 activityCdc42 activationFluid shear stressSmall GTPase Cdc42Protein kinase CzetaGTPase Cdc42Early embryosEndothelial cellsIntegrin dynamicsOrganizing centerCdc42Extracellular matrixLocalized activationFluorescence energy transferMTOC localizationVascular endothelial cellsSingle cellsNovel assayCellsActivationPar6CzetaGolgiEmbryos