2023
Endothelial VEGFR2-PLCγ signaling regulates vascular permeability and anti-tumor immunity through eNOS/Src
Sjöberg E, Melssen M, Richards M, Ding Y, Chanoca C, Chen D, Nwadozi E, Pal S, Love D, Ninchoji T, Shibuya M, Simons M, Dimberg A, Claesson-Welsh L. Endothelial VEGFR2-PLCγ signaling regulates vascular permeability and anti-tumor immunity through eNOS/Src. Journal Of Clinical Investigation 2023, 133: e161366. PMID: 37651195, PMCID: PMC10575733, DOI: 10.1172/jci161366.Peer-Reviewed Original ResearchConceptsEndothelial nitric oxide synthaseRenal cell carcinomaAnti-tumor immunityVascular leakageT cellsEndothelial barrierClear cell renal cell carcinomaCell renal cell carcinomaRegulatory T cellsHelper T cellsNitric oxide synthaseImmune cell activationAntitumor immunityImmunosuppressive cytokinesPoor prognosisCell carcinomaPLCγ pathwayOxide synthaseVascular permeabilityB cellsActivation of PLCγCell activationTumor vesselsDecreased expressionCancer formsEndothelial 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
2022
Multiple Intravenous Bolus Dosing and Invasive Hemodynamic Assessment in a Hypoxia-Induced Mouse Pulmonary Artery Hypertension Model.
Qin L, Jiang B, Zsebo K, Duckers H, Simons M, Chen P. Multiple Intravenous Bolus Dosing and Invasive Hemodynamic Assessment in a Hypoxia-Induced Mouse Pulmonary Artery Hypertension Model. Journal Of Visualized Experiments 2022 PMID: 36440832, DOI: 10.3791/63839.Peer-Reviewed Original ResearchConceptsPulmonary arterial hypertensionInvasive hemodynamic assessmentHemodynamic assessmentPAH modelProgressive life-threatening diseaseGroup 3 diseaseRight ventricle catheterizationSmall pulmonary arteriolesIntravenous bolus dosingNew experimental therapiesLife-threatening diseaseAdministration of compoundsMouse jugular veinHuman clinical manifestationsArterial hypertensionHypertension modelPulmonary arteriolesClinical manifestationsBolus dosingExperimental therapiesIntravenous administrationJugular veinPAH researchMultiple injectionsTime course
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
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 importanceArteriogenesisCellsThe 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 ProteinsEndothelial 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
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 roleEndothelial Nuclear Factor-&kgr;B–Dependent Regulation of Arteriogenesis and Branching
Tirziu D, Jaba IM, Yu P, Larrivée B, Coon BG, Cristofaro B, Zhuang ZW, Lanahan AA, Schwartz MA, Eichmann A, Simons M. Endothelial Nuclear Factor-&kgr;B–Dependent Regulation of Arteriogenesis and Branching. Circulation 2012, 126: 2589-2600. PMID: 23091063, PMCID: PMC3514045, DOI: 10.1161/circulationaha.112.119321.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnimals, NewbornBecaplerminBrainDisease Models, AnimalEndothelial CellsHindlimbHuman Umbilical Vein Endothelial CellsHumansHypoxia-Inducible Factor 1, alpha SubunitIschemiaMiceMice, TransgenicNeovascularization, PathologicNeovascularization, PhysiologicNF-kappa B p50 SubunitProto-Oncogene Proteins c-sisRetinaVascular Endothelial Growth Factor AConceptsNuclear factor-κB activationCollateral formationReduced adhesion molecule expressionHypoxia-inducible factor-1α levelsDistal tissue perfusionVascular endothelial growth factorAdhesion molecule expressionPlatelet-derived growth factor-BBEndothelial growth factorGrowth factor-BBMolecule expressionMonocyte influxCollateral networkTissue perfusionImmature vesselsArterial networkBaseline levelsNFκB activationNuclear factorFactor-BBGrowth factor
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 chainsProteinPR-39 and PR-11 peptides inhibit ischemia-reperfusion injury by blocking proteasome-mediated IκBα degradation
Bao J, Sato K, Li M, Gao Y, Abid R, Aird W, Simons M, Post M. PR-39 and PR-11 peptides inhibit ischemia-reperfusion injury by blocking proteasome-mediated IκBα degradation. AJP Heart And Circulatory Physiology 2001, 281: h2612-h2618. PMID: 11709430, DOI: 10.1152/ajpheart.2001.281.6.h2612.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnti-Bacterial AgentsAntimicrobial Cationic PeptidesCells, CulturedCysteine EndopeptidasesDNA-Binding ProteinsEndothelium, VascularHumansI-kappa B ProteinsIntercellular Adhesion Molecule-1MaleMultienzyme ComplexesMyocardial Reperfusion InjuryMyocardiumNADPH OxidasesNeutrophilsNF-KappaB Inhibitor alphaPeptide FragmentsPeroxidasePhosphoproteinsProteasome Endopeptidase ComplexRatsRats, Sprague-DawleyReactive Oxygen SpeciesUmbilical VeinsVascular Cell Adhesion Molecule-1Ventricular Function, LeftConceptsIschemia-reperfusion injuryB alpha degradationAdhesion molecule-1PR-11Alpha degradationNeutrophil infiltrationMyeloperoxidase activityInfarct sizeMolecule-1Vascular cell adhesion molecule-1Myocardial ischemia-reperfusion injuryIntercellular adhesion molecule-1Cell adhesion molecule-1Ventricular systolic pressureTime of reperfusionIschemia-reperfusion modelMin of ischemiaPR-39Controls 24 hBlood pressureSystolic pressureCardiac functionIntramyocardial injectionIκBα degradationAdhesion moleculesSerial Motion Assessment by Reference Tracking (SMART): Application to Detection of Local Functional Impact of Chronic Myocardial Ischemia
Pearlman J, Gertz Z, Wu Y, Simons M, Post M. Serial Motion Assessment by Reference Tracking (SMART): Application to Detection of Local Functional Impact of Chronic Myocardial Ischemia. Journal Of Computer Assisted Tomography 2001, 25: 558-562. PMID: 11473185, DOI: 10.1097/00004728-200107000-00008.Peer-Reviewed Original ResearchIntramyocardial delivery of FGF2 in combination with radio frequency transmyocardial revascularization
Bao J, Naimark W, Palasis M, Laham R, Simons M, Post M. Intramyocardial delivery of FGF2 in combination with radio frequency transmyocardial revascularization. Catheterization And Cardiovascular Interventions 2001, 53: 429-434. PMID: 11458429, DOI: 10.1002/ccd.1196.Peer-Reviewed Original ResearchTherapeutic coronary angiogenesis: a fronte praecipitium a tergo lupi? *
Simons M. Therapeutic coronary angiogenesis: a fronte praecipitium a tergo lupi? *. AJP Heart And Circulatory Physiology 2001, 280: h1923-h1927. PMID: 11299191, DOI: 10.1152/ajpheart.2001.280.5.h1923.Peer-Reviewed Original ResearchTherapeutic angiogenesis in cardiology using protein formulations
Post M, Laham R, Sellke F, Simons M. Therapeutic angiogenesis in cardiology using protein formulations. Cardiovascular Research 2001, 49: 522-531. PMID: 11166265, DOI: 10.1016/s0008-6363(00)00216-9.Peer-Reviewed Original ResearchAnimalsClinical Trials, Phase I as TopicClinical Trials, Phase II as TopicDisease Models, AnimalEndothelial Growth FactorsFibroblast Growth Factor 2Genetic TherapyGrowth SubstancesHumansInjectionsInjections, IntravenousMyocardial IschemiaNeovascularization, PhysiologicPericardiumPeripheral Vascular DiseasesVascular Endothelial Growth Factor A