2024
SUMOylation Fine-Tunes Endothelial HEY1 in the Regulation of Angiogenesis
Ren R, Ding S, Ma K, Jiang Y, Wang Y, Chen J, Wang Y, Kou Y, Fan X, Zhu X, Qin L, Qiu C, Simons M, Wei X, Yu L. SUMOylation Fine-Tunes Endothelial HEY1 in the Regulation of Angiogenesis. Circulation Research 2024, 134: 203-222. PMID: 38166414, PMCID: PMC10872267, DOI: 10.1161/circresaha.123.323398.Peer-Reviewed Original ResearchDNA-binding capabilityElectrophoretic mobility shift assaysEndothelial cell-specific expressionMobility shift assaysHairy/EnhancerCell-specific expressionPrimary human endothelial cellsNotch pathway componentsE-box promoter elementsEndothelial cellsRegulation of angiogenesisHelix familyPostnatal vascular growthHey1 functionsTranscriptional complexChromatin immunoprecipitationE3 ligaseRTK signalingEmbryonic developmentMatrigel plug assayPromoter elementsBioinformatics analysisShift assaysSUMOylationDNA binding
2023
Endothelial FIS1 DeSUMOylation Protects Against Hypoxic Pulmonary Hypertension
Zhou X, Jiang Y, Wang Y, Fan L, Zhu Y, Chen Y, Wang Y, Zhu Y, Wang H, Pan Z, Li Z, Zhu X, Ren R, Ge Z, Lai D, Lai E, Chen T, Wang K, Liang P, Qin L, Liu C, Qiu C, Simons M, Yu L. Endothelial FIS1 DeSUMOylation Protects Against Hypoxic Pulmonary Hypertension. Circulation Research 2023, 133: 508-531. PMID: 37589160, DOI: 10.1161/circresaha.122.321200.Peer-Reviewed Original ResearchConceptsPulmonary hypertensionHypoxic pulmonary hypertensionPulmonary endothelial functionHuman pulmonary artery endothelial cellsPulmonary artery endothelial cellsPulmonary endotheliumArtery endothelial cellsEndothelial functionEndothelial cellsEndothelial mitochondriaSugen/hypoxia rat modelClinical specimensPulmonary endothelial dysfunctionHypoxia rat modelPulmonary arterial systemHypoxic stressVascular remodeling diseasePrevious clinical researchHuman embryonic stem cell-derived endothelial cellsMitochondrial oxygen consumption rateIntrinsic pathogenesisEndothelial dysfunctionExtracellular acidification rateHypoxic ratsPoor prognosisChylomicrons Regulate Lacteal Permeability and Intestinal Lipid Absorption
Zarkada G, Chen X, Zhou X, Lange M, Zeng L, Lv W, Zhang X, Li Y, Zhou W, Liu K, Chen D, Ricard N, Liao J, Kim Y, Benedito R, Claesson-Welsh L, Alitalo K, Simons M, Ju R, Li X, Eichmann A, Zhang F. Chylomicrons Regulate Lacteal Permeability and Intestinal Lipid Absorption. Circulation Research 2023, 133: 333-349. PMID: 37462027, PMCID: PMC10530007, DOI: 10.1161/circresaha.123.322607.Peer-Reviewed Original ResearchConceptsLymphatic endothelial cellsCell-cell junctionsCytoskeleton contractionMolecular biology approachesSmall GTPase Rac1Cytoskeletal contractilityBiology approachGTPase Rac1Stress fibersA SignalingPI3KLipid uptakePermeability regulationLymphatic permeabilityIntestinal lipid absorptionLEC junctionJunction openingEndothelial cellsLymphatic capillariesVEGFR-2Fundamental mechanismsLymphatic barrierLymphatic vesselsVascular endothelial growthLymphatic junctions
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
2016
Adrenomedullin 2 activates extracellular-signal-regulated kinase in endothelial cells via a protein kinase C α-independent pathway
Guo X, Ju R, Cha C, Simons M. Adrenomedullin 2 activates extracellular-signal-regulated kinase in endothelial cells via a protein kinase C α-independent pathway. F1000Research 2016, 5: 26. DOI: 10.12688/f1000research.2420.1.Peer-Reviewed Original Research
2014
Science Signaling Podcast: 23 September 2014
Simons M, VanHook A. Science Signaling Podcast: 23 September 2014. Science Signaling 2014, 7 DOI: 10.1126/scisignal.2005857.Peer-Reviewed Original ResearchTGF-β signalingMesenchymal transitionReceptor FGFR1Line blood vesselsFibroblast growth factor (FGF) pathwayEndothelial cellsTGF-β receptorCell biologyPolarized cellsGrowth factor pathwaysScience SignalingSignalingBlood vesselsFactor pathwayVascular homeostasisFGFNormal functionCellsFGFR1EndMTNormal conditionsMicroRNAsSenior authorBiologyHomeostasisPTP1b 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 recovery
2013
Endothelial Cell–Dependent Regulation of Arteriogenesis
Moraes F, Paye J, Mac Gabhann F, Zhuang ZW, Zhang J, Lanahan AA, Simons M. Endothelial Cell–Dependent Regulation of Arteriogenesis. Circulation Research 2013, 113: 1076-1086. PMID: 23897694, PMCID: PMC3865810, DOI: 10.1161/circresaha.113.301340.Peer-Reviewed Original ResearchConceptsAdult arteriogenesisCell-autonomous fashionGrowth factor signalingMouse linesCell-autonomous effectsKnockin mouse lineMorphogenetic defectsArterial morphogenesisCell type-specific deletionFactor signalingCell typesCre-driver mouse linesSynectinAttractive therapeutic strategyOcclusive atherosclerotic diseaseMuscle cellsEndothelial cellsRegulationArterial conduitsAtherosclerotic diseaseTherapeutic strategiesAdult miceClinical importanceArteriogenesisCellsEndothelial ERK signaling controls lymphatic fate specification
Deng Y, Atri D, Eichmann A, Simons M. Endothelial ERK signaling controls lymphatic fate specification. Journal Of Clinical Investigation 2013, 123: 1202-1215. PMID: 23391722, PMCID: PMC3582116, DOI: 10.1172/jci63034.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAortaBody PatterningButadienesCells, CulturedEndothelium, LymphaticExtracellular Signal-Regulated MAP KinasesFemaleGene ExpressionGene Expression Regulation, DevelopmentalHomeodomain ProteinsHuman Umbilical Vein Endothelial CellsHumansLymphangiectasisLymphangiogenesisMaleMAP Kinase Signaling SystemMiceMice, TransgenicMutation, MissenseNitrilesProto-Oncogene Proteins c-aktProto-Oncogene Proteins c-rafSOXF Transcription FactorsTumor Suppressor ProteinsUp-RegulationVascular Endothelial Growth Factor Receptor-3ConceptsFate specificationERK activationSOX18 expressionEndothelial cellsLymphatic endothelial cellsInhibition of ERKLymphatic fateDifferentiation programNoonan syndromeLymphatic phenotypeInducible expressionRAF1 geneMolecular eventsFunction mutationsProx1 expressionVenous endothelial cellsCardinal veinERKExpressionLymphatic vesselsKey roleRelated diseasesSOX18ActivationExcessive production
2012
Syndecan 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 ResearchConceptsFGF 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
2010
Aging‐induced collateral impairment: role of arterial rarefaction, decreased eNOS expression/signaling, and increased susceptibility of endothelial cells to apoptosis
Epstein S, Wang J, Peng X, Zhuang Z, Simons M, Xue Z, Burnett M. Aging‐induced collateral impairment: role of arterial rarefaction, decreased eNOS expression/signaling, and increased susceptibility of endothelial cells to apoptosis. The FASEB Journal 2010, 24: 294.3-294.3. DOI: 10.1096/fasebj.24.1_supplement.294.3.Peer-Reviewed Original ResearchWild-type miceEndothelial cellsOld miceEndothelial nitric oxide synthase proteinNitric oxide synthase proteinOld wild-type micePositive animal studiesYoung wild-type miceENOS-KO miceENOS knockout miceDisappointing clinical resultsPre-existing arteriolesVessel phenotypeENOS expressionENOS proteinKO miceC57 miceClinical resultsYoung miceArteriolar rarefactionAge-induced changesKnockout miceAnimal studiesTherapeutic interventionsAngiogenesis therapy
2008
Arterial branching morphogenesis
Simons M. Arterial branching morphogenesis. The FASEB Journal 2008, 22: 520.1-520.1. DOI: 10.1096/fasebj.22.1_supplement.520.1.Peer-Reviewed Original ResearchVariety of signalsArterial morphogenesisArterial differentiationBranching morphogenesisEmbryonic developmentZebrafish modelPDGF stimulationOrgan growthAdult tissuesGene expressionIntracellular signalingMorphogenesisCell typesMolecular defectsTree sizeKey eventsEndothelial cellsRegulationAbnormal activationKey roleObvious importanceActivationSynectinRac1Signaling
2007
Introductory Essay: Endothelial Cell Coupling
Simons M. Introductory Essay: Endothelial Cell Coupling. 2007, 627-631. DOI: 10.1017/cbo9780511546198.070.Peer-Reviewed Original ResearchSerine/threonine kinaseG protein-coupled receptorsEndothelial cellsTyrosine kinase receptorsAdhesion moleculesThreonine kinaseKinase receptorsEndothelial cell couplingExtracellular matrixSoluble ligandsTight junctionsGrowth factorCell couplingCellsEC interactionsCellular adhesion moleculesKinaseSyndecansReceptorsVessel wallIntegrinsMoleculesSolid phase environmentsBlood cellsAppropriate responseEndothelial Activation and Neointimal Hyperplasia: A Double-Edged Sword
Khurana R, Simons M. Endothelial Activation and Neointimal Hyperplasia: A Double-Edged Sword. 2007, 75-84. DOI: 10.1007/1-4020-5955-8_4.Peer-Reviewed Original ResearchActivated endothelial cellsAngiogenic growth factorsNeointimal thickeningEndothelial cellsGrowth factorPercutaneous revascularization proceduresVascular smooth muscle cellsNumerous preclinical modelsVasa vasorum neovascularizationEndothelial cell activationVessel wall remodelingSmooth muscle cellsRole of VEGFPotent angiogenic growth factorRevascularization proceduresStent eraEndothelial activationInflammatory cellsNew capillary growthParacrine sourceVascular responsesNeointimal accumulationEndothelial repairEndovascular proceduresPreclinical modelsSynectin‐dependent suppression of basal Rac1 activity is reversed by a signaling pathway involving PKCalpha and RhoG
Elfenbein A, Simons M. Synectin‐dependent suppression of basal Rac1 activity is reversed by a signaling pathway involving PKCalpha and RhoG. The FASEB Journal 2007, 21: lb11-lb12. DOI: 10.1096/fasebj.21.6.lb11-d.Peer-Reviewed Original ResearchFibroblast growth factorEndothelial cellsHigh-affinity tyrosine kinase receptorsLow baseline levelsRac1 activitySerum-starved endothelial cellsHigh-affinity receptorTyrosine kinase receptorsBaseline levelsGrowth factorInhibitor-1Endothelial cell migrationHeparan sulfate proteoglycanDissociation inhibitor 1Kinase receptorsMigratory responseEarly eventsNovel roleSulfate proteoglycanCell migration
2006
Syndecan‐4 plays a key role in the phosphorylation of protein kinase B / Akt
Partovian C, Simons M. Syndecan‐4 plays a key role in the phosphorylation of protein kinase B / Akt. The FASEB Journal 2006, 20: a1080-a1080. DOI: 10.1096/fasebj.20.5.a1080-a.Peer-Reviewed Original ResearchPhosphoinositide-dependent kinase 1Syndecan-4Akt phosphorylationProtein kinase B/AktPhosphorylation of Thr308Hydrophobic motifActivation loopRaft fractionsEndothelial cellsKinase 1Akt activationPhosphorylationMammalian targetSyndecansThr308AktGrowth factorCentral roleRegulationCellsKey roleMajor roleRictorNumber of processesSer473Granzyme B‐dependent Matrix Degradation Generates Anti‐Angiostatic Activity in Scleroderma Patients
Mulligan‐Kehoe M, Drinane M, Hummers L, Hall A, Rosen A, Wigley F, Simons M. Granzyme B‐dependent Matrix Degradation Generates Anti‐Angiostatic Activity in Scleroderma Patients. The FASEB Journal 2006, 20: a1099-a1099. DOI: 10.1096/fasebj.20.5.a1099-a.Peer-Reviewed Original ResearchSSc patientsRA patientsScleroderma patientsGranzyme BSystemic connective tissue diseasesExtensive vascular componentConnective tissue diseasePAI-1 levelsNormal control patientsAngiostatin K1-3Impaired wound healingAnti-angiogenic factorsAnti-angiogenic activityNormal endothelial cellsAberrant microvasculatureControl patientsRheumatoid arthritisTissue diseaseVascular abnormalitiesUncertain etiologyVascular componentPatientsEndothelial cellsEndothelial cell migrationWound healingThe FGF system positively regulates vascular integrity after ischemic injury
Murakami M, Moodie K, Zhuang Z, Ko I, Stan R, Simons M. The FGF system positively regulates vascular integrity after ischemic injury. The FASEB Journal 2006, 20: a636-a636. DOI: 10.1096/fasebj.20.4.a636-b.Peer-Reviewed Original ResearchIschemic injuryFemoral arteryTen-week-old miceVascular integrityEndothelial cellsRight femoral arteryTissue cGMP levelsFemoral artery ligationGrowth factor systemFibroblast growth factor (FGF) systemRat femoral arteryConditional transgenic mouse lineTransgenic mouse lineFGF systemAortic endothelial cellsEndothelial barrier functionBovine aortic endothelial cellsIschemic sideArtery ligationVascular leakageHindlimb ischemiaOld miceIschemic regionCGMP levelsFoot loss
1999
Myocyte-dependent Regulation of Endothelial Cell Syndecan-4 Expression ROLE OF TNF-α*
Zhang Y, Pasparakis M, Kollias G, Simons M. Myocyte-dependent Regulation of Endothelial Cell Syndecan-4 Expression ROLE OF TNF-α*. Journal Of Biological Chemistry 1999, 274: 14786-14790. PMID: 10329676, DOI: 10.1074/jbc.274.21.14786.Peer-Reviewed Original ResearchConceptsSyndecan-4 expressionECV cellsProtein kinase C alphaCardiac myocytesGene familySyndecan-4 mRNATNF-alphaPosttranscriptional mechanismsGene expressionPrimary cardiac myocytesUnique memberC alphaHuman endothelial cellsSyndecan-4Western analysisMouse cardiac myocytesSyndecan-4 levelsNormal myoblastsDependent mannerNF-kappaBExpressionH9c2 cellsHypoxic conditionsTumor necrosisEndothelial cells