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 studiesCellular stiffness sensing through talin 1 in tissue mechanical homeostasis
Chanduri M, Kumar A, Weiss D, Emuna N, Barsukov I, Shi M, Tanaka K, Wang X, Datye A, Kanyo J, Collin F, Lam T, Schwarz U, Bai S, Nottoli T, Goult B, Humphrey J, Schwartz M. Cellular stiffness sensing through talin 1 in tissue mechanical homeostasis. Science Advances 2024, 10: eadi6286. PMID: 39167642, PMCID: PMC11338229, DOI: 10.1126/sciadv.adi6286.Peer-Reviewed Original ResearchConceptsTissue mechanical homeostasisStiffness sensingExtracellular matrixTalin-1Mechanical homeostasisExtracellular matrix mechanicsIncreased cell spreadingCell spreadingTalinMutationsCellular sensingFibrillar collagenReduced axial stiffnessTissue mechanical propertiesMechanical propertiesAxial stiffnessCompliant substratesHomeostasisRupture pressureArp2/3ARPC5LStiffnessHomeostasis hypothesisResident cellsTissue stiffnessAfadin–nectin forces its way to the front
Sebbagh M, Schwartz M. Afadin–nectin forces its way to the front. Journal Of Cell Biology 2024, 223: e202403177. PMID: 38563860, PMCID: PMC10988649, DOI: 10.1083/jcb.202403177.Peer-Reviewed Original Research
2023
Altered Integrin Signaling in Thoracic Aortopathy
Humphrey J, Schwartz M. Altered Integrin Signaling in Thoracic Aortopathy. Arteriosclerosis Thrombosis And Vascular Biology 2023, 43: 1154-1156. PMID: 37165879, DOI: 10.1161/atvbaha.123.319404.Commentaries, Editorials and LettersTLN1 contains a cancer-associated cassette exon that alters talin-1 mechanosensitivity
Gallego-Paez L, Edwards W, Chanduri M, Guo Y, Koorman T, Lee C, Grexa N, Derksen P, Yan J, Schwartz M, Mauer J, Goult B. TLN1 contains a cancer-associated cassette exon that alters talin-1 mechanosensitivity. Journal Of Cell Biology 2023, 222: e202209010. PMID: 36880935, PMCID: PMC9997659, DOI: 10.1083/jcb.202209010.Peer-Reviewed Original ResearchConceptsExon 17bTerminal FERM domainVinculin bindingFERM domainSwitch domainAdhesion dynamicsCassette exonsSplicing analysisAdapter proteinTLN1Single isoformIsoform switchTalin-1Amino acidsFrame insertionExonsBiochemical analysisIsoformsProteinExon 17CytoskeletonGenesMechanotransductionDomainIntegrins
2022
The UIP/IPF fibroblastic focus is a collagen biosynthesis factory embedded in a distinct extracellular matrix
Herrera JA, Dingle L, Fernandez M, Venkateswaran RV, Blaikley JF, Lawless C, Schwartz MA. The UIP/IPF fibroblastic focus is a collagen biosynthesis factory embedded in a distinct extracellular matrix. JCI Insight 2022, 7: e156115. PMID: 35852874, PMCID: PMC9462507, DOI: 10.1172/jci.insight.156115.Peer-Reviewed Original ResearchA 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 pathwayMicroRNAs in Mechanical Homeostasis
Herrera JA, Schwartz MA. MicroRNAs in Mechanical Homeostasis. Cold Spring Harbor Perspectives In Medicine 2022, 12: a041220. PMID: 35379658, PMCID: PMC9380736, DOI: 10.1101/cshperspect.a041220.Peer-Reviewed Original Research
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 proliferationDiseaseProgressionActivation 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) sensingPhosphorylationALK5Smad2/3Epistatic interaction of PDE4DIP and DES mutations in familial atrial fibrillation with slow conduction
Ziki M, Bhat N, Neogi A, Driscoll TP, Ugwu N, Liu Y, Smith E, Abboud JM, Chouairi S, Schwartz MA, Akar JG, Mani A. Epistatic interaction of PDE4DIP and DES mutations in familial atrial fibrillation with slow conduction. Human Mutation 2021, 42: 1279-1293. PMID: 34289528, PMCID: PMC8434967, DOI: 10.1002/humu.24265.Peer-Reviewed Original ResearchConceptsEarly-onset atrial fibrillationAtrial fibrillationHeart blockFamilial atrial fibrillationSlow conductionDES mutationsSlow atrial fibrillationWhole-exome sequencingConduction diseaseIsoproterenol stimulationExome sequencingGenetic causePathogenic mutationsPDE4DIPReduced colocalizationHigh penetranceGenetic screeningUnrelated kindredsFibrillationPKA phosphorylationDesmin geneEpistatic interactionsT substitutionKindredsPDE4DDefective Flow-Migration Coupling Causes Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia
Park H, Furtado J, Poulet M, Chung M, Yun S, Lee S, Sessa WC, Franco CA, Schwartz MA, Eichmann A. Defective Flow-Migration Coupling Causes Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia. Circulation 2021, 144: 805-822. PMID: 34182767, PMCID: PMC8429266, DOI: 10.1161/circulationaha.120.053047.Peer-Reviewed Original ResearchConceptsActivin receptor-like kinase 1Hereditary hemorrhagic telangiectasiaHemorrhagic telangiectasiaVascular malformationsArteriovenous malformationsBlood flowGrowth factor receptor 2Endothelial growth factor receptor 2Vascular endothelial growth factor receptor 2Factor receptor 2Receptor-like kinase 1New potential targetsYAP/TAZ nuclear translocationDeficient miceTransmembrane serine-threonine kinase receptorsDevastating disorderAlk1 deletionReceptor 2Pharmacologic inhibitionCre linesPostnatal retinaMalformationsSerine-threonine kinase receptorsEndothelial cell migrationNuclear translocationAltered endocytosis in cellular senescence
Shin EY, Soung NK, Schwartz MA, Kim EG. Altered endocytosis in cellular senescence. Ageing Research Reviews 2021, 68: 101332. PMID: 33753287, PMCID: PMC8131247, DOI: 10.1016/j.arr.2021.101332.Peer-Reviewed Original Research
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 retentionFilamin A mediates isotropic distribution of applied force across the actin network
Kumar A, Shutova MS, Tanaka K, Iwamoto DV, Calderwood DA, Svitkina TM, Schwartz MA. Filamin A mediates isotropic distribution of applied force across the actin network. Journal Of Cell Biology 2019, 218: 2481-2491. PMID: 31315944, PMCID: PMC6683746, DOI: 10.1083/jcb.201901086.Peer-Reviewed Original ResearchConceptsTalin tension sensorStress fibersActin networkFilamin ACortical actin networkCortical actin filamentsIntegrin-mediated adhesionActin cytoskeletonFocal adhesionsCortical actinFLNA knockdownActin filamentsTalinKnockdownCell sensingDirection of stretchTension sensorPhysiology of muscleUniaxial stretchForce transmissionCytoskeletonStrainsStretchAdhesionReexpressionCaveolin-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 modelAtherosclerosisInflammationMicroRNA-dependent regulation of biomechanical genes establishes tissue stiffness homeostasis
Moro A, Driscoll TP, Boraas LC, Armero W, Kasper DM, Baeyens N, Jouy C, Mallikarjun V, Swift J, Ahn SJ, Lee D, Zhang J, Gu M, Gerstein M, Schwartz M, Nicoli S. MicroRNA-dependent regulation of biomechanical genes establishes tissue stiffness homeostasis. Nature Cell Biology 2019, 21: 348-358. PMID: 30742093, PMCID: PMC6528464, DOI: 10.1038/s41556-019-0272-y.Peer-Reviewed Original ResearchConceptsArgonaute 2MicroRNA-dependent regulationMechanical homeostasisMicroRNA recognition elementsExtracellular matrix proteinsZebrafish finsMicroRNA familiesTarget mRNAsVertebrate tissuesHyper-contractile phenotypesRegulatory pathwaysUntranslated regionRecognition elementMatrix proteinsComprehensive identificationCaM mRNAConnective tissue growth factorExtracellular matrix depositionHomeostasisTissue growth factorMRNAFibroblast cellsMicroRNAsGrowth factorSoft substratesARHGAP18: 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 abilityTranslocating transcription factors in fluid shear stress-mediated vascular remodeling and disease
Min E, Schwartz MA. Translocating transcription factors in fluid shear stress-mediated vascular remodeling and disease. Experimental Cell Research 2019, 376: 92-97. PMID: 30633880, PMCID: PMC8211025, DOI: 10.1016/j.yexcr.2019.01.005.Peer-Reviewed Original Research
2018
Talin as a mechanosensitive signaling hub
Goult BT, Yan J, Schwartz MA. Talin as a mechanosensitive signaling hub. Journal Of Cell Biology 2018, 217: 3776-3784. PMID: 30254032, PMCID: PMC6219721, DOI: 10.1083/jcb.201808061.Peer-Reviewed Original ResearchConceptsSignaling hubsExtracellular matrixRod domainTalin rod domainIntegrin β subunitsDifferent protein interactionsLong rod domainSwitch-like behaviorActin cytoskeletonCytoplasmic domainCytoplasmic proteinsProtein interactionsHelical bundleGlobular head domainTalin functionTransmembrane receptorsHelix bundleΒ-subunitHead domainIntegrin familyTalinCell adhesionIndividual domainsRecent evidenceDomain