2023
Acetate controls endothelial-to-mesenchymal transition
Zhu X, Wang Y, Soaita I, Lee H, Bae H, Boutagy N, Bostwick A, Zhang R, Bowman C, Xu Y, Trefely S, Chen Y, Qin L, Sessa W, Tellides G, Jang C, Snyder N, Yu L, Arany Z, Simons M. Acetate controls endothelial-to-mesenchymal transition. Cell Metabolism 2023, 35: 1163-1178.e10. PMID: 37327791, PMCID: PMC10529701, DOI: 10.1016/j.cmet.2023.05.010.Peer-Reviewed Original ResearchMeSH KeywordsEndothelial CellsEndotheliumHumansSignal TransductionTransforming Growth Factor betaVascular DiseasesConceptsTGF-β signalingChronic vascular diseaseTGF-β receptor ALK5Mesenchymal transitionInduction of EndMTVascular diseaseMolecular basisPositive feedback loopReceptor ALK5Cellular levelSMADs 2Novel targetEndMT inductionMetabolic modulationMetabolic basisFibrotic stateSignalingPotential treatmentEndMTTGFDiseaseActivationInductionACSS2PDK4
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 retention
2018
SUMOylation of VEGFR2 regulates its intracellular trafficking and pathological angiogenesis
Zhou HJ, Xu Z, Wang Z, Zhang H, Zhuang Z, Simons M, Min W. SUMOylation of VEGFR2 regulates its intracellular trafficking and pathological angiogenesis. Nature Communications 2018, 9: 3303. PMID: 30120232, PMCID: PMC6098000, DOI: 10.1038/s41467-018-05812-2.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCorneaCysteine EndopeptidasesDiabetes MellitusEndopeptidasesGene DeletionGene Knock-In TechniquesGene SilencingGolgi ApparatusHuman Umbilical Vein Endothelial CellsHumansIntracellular SpaceMaleMice, Inbred C57BLMice, KnockoutNeovascularization, PathologicProtein TransportRetinaSignal TransductionSUMO-1 ProteinSumoylationVascular Endothelial Growth Factor AVascular Endothelial Growth Factor Receptor-2ConceptsPathological angiogenesisPotential therapeutic targetRegulation of VEGFR2Non-sumoylated formEndothelial-specific deletionDiabetic miceHindlimb ischemiaTherapeutic targetDiabetic settingControl of angiogenesisEndothelial cellsAngiogenesisVEGFR2Surface expressionVEGFR2 activityTissue repairSENP1
2014
Fibroblast growth factor receptor 1 is a key inhibitor of TGFβ signaling in the endothelium
Chen PY, Qin L, Tellides G, Simons M. Fibroblast growth factor receptor 1 is a key inhibitor of TGFβ signaling in the endothelium. Science Signaling 2014, 7: ra90. PMID: 25249657, DOI: 10.1126/scisignal.2005504.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell TransdifferentiationCoronary VesselsEndothelium, VascularExtracellular MatrixFibroblastsGraft RejectionHeart TransplantationHeterograftsHindlimbHuman Umbilical Vein Endothelial CellsHumansIschemiaMesodermMiceMice, Mutant StrainsMicroRNAsMuscle, Smooth, VascularNeointimaReceptor, Fibroblast Growth Factor, Type 1Receptors, Fibroblast Growth FactorSignal TransductionSmad2 ProteinTransforming Growth Factor betaTransplantation ChimeraConceptsFibroblast growth factor receptor 1Growth factor receptor 1Factor receptor 1Extracellular matrixSmooth muscle cellsMuscle cellsEndothelial cell-specific knockoutKey regulatorReceptor 1TGFβ signalingCell-specific knockoutDecreased abundanceMesenchymal transitionKey inhibitorVascular homeostasisGrowth factorDevelopment of EndMTRecurrence of stenosisTGFβGrowth of neointimaCellsNeointima formationEndMTVascular lumenSignalingPTP1b Is a Physiologic Regulator of Vascular Endothelial Growth Factor Signaling in Endothelial Cells
Lanahan AA, Lech D, Dubrac A, Zhang J, Zhuang ZW, Eichmann A, Simons M. PTP1b Is a Physiologic Regulator of Vascular Endothelial Growth Factor Signaling in Endothelial Cells. Circulation 2014, 130: 902-909. PMID: 24982127, PMCID: PMC6060619, DOI: 10.1161/circulationaha.114.009683.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAortaCell MovementCell ProliferationDisease Models, AnimalEndothelial CellsFemaleHindlimbHuman Umbilical Vein Endothelial CellsIschemiaMaleMiceMice, Mutant StrainsNeovascularization, PhysiologicPrimary Cell CultureProtein Tyrosine Phosphatase, Non-Receptor Type 1RNA, Small InterferingSignal TransductionVascular Endothelial Growth Factor AVascular Endothelial Growth Factor Receptor-2ConceptsPhosphotyrosine phosphatase 1BVascular endothelial growth factor receptor 2 signalingExtracellular signal-regulated kinaseGrowth factor signalingVEGF-dependent activationSignal-regulated kinaseNull miceVascular endothelial growth factor signalingRegulation of angiogenesisEndothelial traffickingEndothelial-specific deletionFactor signalingEndothelial VEGFR2Phosphatase 1BEndothelial cellsKey regulatorReceptor 2 signalingVEGFR2 signalingSignalingImportant roleEndothelial knockoutPhysiologic regulatorHindlimb ischemia mouse modelRegulationImpaired blood flow recoveryThe docking protein FRS2α is a critical regulator of VEGF receptors signaling
Chen PY, Qin L, Zhuang ZW, Tellides G, Lax I, Schlessinger J, Simons M. The docking protein FRS2α is a critical regulator of VEGF receptors signaling. Proceedings Of The National Academy Of Sciences Of The United States Of America 2014, 111: 5514-5519. PMID: 24706887, PMCID: PMC3992672, DOI: 10.1073/pnas.1404545111.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAnimalsCell MovementDNA PrimersEndothelial CellsGene Expression ProfilingGenetic VectorsHEK293 CellsHuman Umbilical Vein Endothelial CellsHumansImmunoblottingImmunohistochemistryImmunoprecipitationLaser-Doppler FlowmetryLentivirusMembrane ProteinsMiceReal-Time Polymerase Chain ReactionReceptors, Vascular Endothelial Growth FactorSignal TransductionX-Ray MicrotomographyConceptsLymphatic endothelial cell migrationFibroblast growth factor receptor substrate 2Growth factor receptor substrate 2Cognate receptor tyrosine kinasesFactor receptor substrate 2Receptor kinase signalingVascular endothelial growth factorPostnatal vascular developmentReceptor tyrosine kinasesEndothelial cell migrationKinase signalingEndothelial-specific deletionAdult angiogenesisVEGF receptorsTyrosine kinaseCritical regulatorVascular developmentFRS2αSubstrate 2Cell migrationDependent activationCritical roleUnidentified componentsGrowth factorEndothelial growth factor
2013
The Neuropilin 1 Cytoplasmic Domain Is Required for VEGF-A-Dependent Arteriogenesis
Lanahan A, Zhang X, Fantin A, Zhuang Z, Rivera-Molina F, Speichinger K, Prahst C, Zhang J, Wang Y, Davis G, Toomre D, Ruhrberg C, Simons M. The Neuropilin 1 Cytoplasmic Domain Is Required for VEGF-A-Dependent Arteriogenesis. Developmental Cell 2013, 25: 156-168. PMID: 23639442, PMCID: PMC3774154, DOI: 10.1016/j.devcel.2013.03.019.Peer-Reviewed Original ResearchAnimalsArteriesCells, CulturedCytoplasmEndocytosisEndosomesEndothelium, VascularMAP Kinase Signaling SystemMiceMorphogenesisNeovascularization, PathologicNeuropilin-1PhosphorylationSignal TransductionTransferrinVascular Endothelial Growth Factor AVascular Endothelial Growth Factor Receptor-2Vesicular Transport Proteins
2012
FGF Regulates TGF-β Signaling and Endothelial-to-Mesenchymal Transition via Control of let-7 miRNA Expression
Chen PY, Qin L, Barnes C, Charisse K, Yi T, Zhang X, Ali R, Medina PP, Yu J, Slack FJ, Anderson DG, Kotelianski V, Wang F, Tellides G, Simons M. FGF Regulates TGF-β Signaling and Endothelial-to-Mesenchymal Transition via Control of let-7 miRNA Expression. Cell Reports 2012, 2: 1684-1696. PMID: 23200853, PMCID: PMC3534912, DOI: 10.1016/j.celrep.2012.10.021.Peer-Reviewed Original ResearchConceptsFibroblast growth factorEndo-MTMesenchymal transitionGrowth factorNormal endothelial functionBlood vessel functionTGF-β signalingEndothelial functionVascular pathologyEndothelial homeostasisNeointima formationVessel functionΒ ligandMiRNA levelsMiRNA expressionActivationExpressionUnexpected roleSyndecan 4 Regulates FGFR1 Signaling in Endothelial Cells by Directing Macropinocytosis
Elfenbein A, Lanahan A, Zhou TX, Yamasaki A, Tkachenko E, Matsuda M, Simons M. Syndecan 4 Regulates FGFR1 Signaling in Endothelial Cells by Directing Macropinocytosis. Science Signaling 2012, 5: ra36. PMID: 22569333, PMCID: PMC3827948, DOI: 10.1126/scisignal.2002495.Peer-Reviewed Original ResearchMeSH KeywordsEndotheliumHeLa CellsHumansMAP Kinase Signaling SystemPinocytosisReceptor, Fibroblast Growth Factor, Type 1Signal TransductionSyndecan-4ConceptsFGF receptor 1Mitogen-activated protein kinaseFibroblast growth factor-2MAPK signalingSyndecan-4Inhibition of Rab5Receptor tyrosine kinasesEndothelial cell migrationHeparan sulfate proteoglycanSignal transductionProtein kinaseFGF2 stimulationEndothelial cellsMAPK activationTyrosine kinaseGrowth factor 2Genetic knockoutCell migrationReceptor complexMacropinocytosisClasses of receptorsSignalingRab5Factor 2Sulfate proteoglycan
2001
Syndecan-4-mediated signalling
Simons M, Horowitz A. Syndecan-4-mediated signalling. Cellular Signalling 2001, 13: 855-862. PMID: 11728825, DOI: 10.1016/s0898-6568(01)00190-5.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsFibroblast Growth FactorsIsoenzymesMacromolecular SubstancesMembrane GlycoproteinsModels, BiologicalMolecular Sequence DataPhosphatidylinositol 4,5-DiphosphatePhosphorylationProtein Kinase CProtein Kinase C-alphaProtein Structure, TertiaryProteoglycansSignal TransductionSyndecan-4ConceptsSyndecan familySyndecan-4Carboxy-terminal PDZPDZ adaptor proteinsUnique signaling functionsProtein kinase C alphaCore proteinExtracellular matrix proteinsHeparan sulfate chainsSoluble growth factorsTyrosine kinase receptorsAdaptor proteinCytoplasmic tailSignaling functionsTransmembrane proteoglycansProteoglycan functionMultimolecular complexesC alphaMatrix proteinsKinase receptorsPostsynaptic density-95Zona occludensGlycosaminoglycan chainsSulfate chainsProtein
2000
Molecular multitasking: statins lead to more arteries, less plaque
Simons M. Molecular multitasking: statins lead to more arteries, less plaque. Nature Medicine 2000, 6: 965-966. PMID: 10973306, DOI: 10.1038/79646.Peer-Reviewed Original ResearchAnticholesteremic AgentsArteriosclerosisEnzyme ActivationHydroxymethylglutaryl-CoA Reductase InhibitorsNeovascularization, PhysiologicNitric Oxide SynthaseNitric Oxide Synthase Type IIIProtein KinasesProtein Serine-Threonine KinasesProto-Oncogene ProteinsProto-Oncogene Proteins c-aktSignal TransductionSimvastatin
1999
The Role of Syndecan Cytoplasmic Domain in Basic Fibroblast Growth Factor-dependent Signal Transduction*
Volk R, Schwartz J, Li J, Rosenberg R, Simons M. The Role of Syndecan Cytoplasmic Domain in Basic Fibroblast Growth Factor-dependent Signal Transduction*. Journal Of Biological Chemistry 1999, 274: 24417-24424. PMID: 10446222, DOI: 10.1074/jbc.274.34.24417.Peer-Reviewed Original ResearchConceptsCytoplasmic domainBasic fibroblast growth factorSyndecan-4Ectoplasmic domainSignal transductionSyndecan-4 cytoplasmic domainVector-transduced cellsSyndecan cytoplasmic domainsGrowth factor-dependent signal transductionHeparan sulfate attachment sitesTransmembrane/cytoplasmic domainsGlycosylphosphatidylinositol (GPI) anchor sequenceImmortalized human cellsGlypican-1Full-length sequencesAddition of bFGFCytoplasmic tailAnchor sequenceChimeric proteinMigration of cellsFibroblast growth factorLow-serum mediumHuman cellsGrowth assaysVC cells
1998
Phosphorylation of the Cytoplasmic Tail of Syndecan-4 Regulates Activation of Protein Kinase Cα*
Horowitz A, Simons M. Phosphorylation of the Cytoplasmic Tail of Syndecan-4 Regulates Activation of Protein Kinase Cα*. Journal Of Biological Chemistry 1998, 273: 25548-25551. PMID: 9748216, DOI: 10.1074/jbc.273.40.25548.Peer-Reviewed Original Research