2024
Akt is a mediator of artery specification during zebrafish development
Zhou W, Ghersi J, Ristori E, Semanchik N, Prendergast A, Zhang R, Carneiro P, Baldissera G, Sessa W, Nicoli S. Akt is a mediator of artery specification during zebrafish development. Development 2024, 151: dev202727. PMID: 39101673, PMCID: PMC11441982, DOI: 10.1242/dev.202727.Peer-Reviewed Original ResearchArterial specificationEndothelial cellsVascular endothelial growth factor ADorsal aortaEndothelial growth factor ASingle-cell RNA sequencing analysisGrowth factor AArtery endothelial cellsEmbryonic cardiovascular systemConstitutively active Akt1Ligand-independent activationActivation of NotchArteriovenous malformationsCongenital malformationsRNA sequencing analysisVEGF-AProtein kinase BUpstream of NotchSequence analysisCardiovascular developmentSpecific expressionAkt kinaseActive Akt1Zebrafish developmentCardiovascular systemZFYVE21 promotes endothelial nitric oxide signaling and vascular barrier function in the kidney during aging
Jiang Q, Song G, He L, Li X, Jiang B, Wang Q, Wang S, Kim C, Barkestani M, Lopez R, Fan M, Wanniarachchi K, Quaranta M, Tian X, Mani A, Gonzalez A, Goodwin J, Sessa W, Ishibe S, Jane-Wit D. ZFYVE21 promotes endothelial nitric oxide signaling and vascular barrier function in the kidney during aging. Kidney International 2024, 106: 419-432. PMID: 38797325, PMCID: PMC11343665, DOI: 10.1016/j.kint.2024.05.007.Peer-Reviewed Original ResearchVascular barrier functionEndothelial cellsReduced endothelial nitric oxideRegulator of vascular barrier functionEndothelial nitric oxide signalingENOS activityEndosome-associated proteinsBarrier functionKidney organ culturesEndothelial nitric oxideAkt-dependent mannerNitric oxide donorGTPase Rab5Nitric oxide signalingZFYVE21Live cell imagingKidney insufficiencyReporter miceTrafficking mechanismsAccelerated aging phenotypeKnockout miceInterstitial edemaKidney functionVesicular populationOxide donor
2023
TNFα increases the degradation of pyruvate dehydrogenase kinase 4 by the Lon protease to support proinflammatory genes
Boutagy N, Fowler J, Grabinska K, Cardone R, Sun Q, Vazquez K, Whalen M, Zhu X, Chakraborty R, Martin K, Simons M, Romanoski C, Kibbey R, Sessa W. TNFα increases the degradation of pyruvate dehydrogenase kinase 4 by the Lon protease to support proinflammatory genes. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2218150120. PMID: 37695914, PMCID: PMC10515159, DOI: 10.1073/pnas.2218150120.Peer-Reviewed Original ResearchConceptsPyruvate dehydrogenase kinase 4Dehydrogenase kinase 4Lon proteasePyruvate dehydrogenase activityHistone acetylationMitochondrial metabolismKinase 4Specific gene lociPDH fluxEndothelial cellsSiRNA-mediated knockdownAcetyl-CoA generationLysine 27Gene transcriptionTCA fluxRNA sequencingHuman umbilical vein endothelial cellsProtein degradationHistone 3Gene locusUmbilical vein endothelial cellsNF-κB-dependent mechanismTricarboxylic acid cycle fluxVein endothelial cellsActive subunitSREBP2 regulates the endothelial response to cytokines via direct transcriptional activation of KLF6
Fowler J, Boutagy N, Zhang R, Horikami D, Whalen M, Romanoski C, Sessa W. SREBP2 regulates the endothelial response to cytokines via direct transcriptional activation of KLF6. Journal Of Lipid Research 2023, 64: 100411. PMID: 37437844, PMCID: PMC10407908, DOI: 10.1016/j.jlr.2023.100411.Peer-Reviewed Original ResearchConceptsDirect transcriptional activationTranscriptional activationEndothelial cellsChemokine expressionChromatin immunoprecipitation sequencingCholesterol homeostasisSterol-responsive genesPro-inflammatory chemokinesLipid-lowering drugsAdaptive immune responsesPro-inflammatory genesTranscription factor SREBP2Endogenous cholesterol synthesisImmunoprecipitation sequencingResponsive genesMechanism of actionPromoter regionCardiovascular riskAtherosclerotic diseaseInflammatory phenotypeImmune modulationCardiovascular diseaseImmune responseInflammatory stimuliI interferonAn optogenetic-phosphoproteomic study reveals dynamic Akt1 signaling profiles in endothelial cells
Zhou W, Li W, Wang S, Salovska B, Hu Z, Tao B, Di Y, Punyamurtula U, Turk B, Sessa W, Liu Y. An optogenetic-phosphoproteomic study reveals dynamic Akt1 signaling profiles in endothelial cells. Nature Communications 2023, 14: 3803. PMID: 37365174, PMCID: PMC10293293, DOI: 10.1038/s41467-023-39514-1.Peer-Reviewed Original ResearchConceptsPhosphorylation sitesSerine/threonine kinase AktMass spectrometry-based phosphoproteomicsThreonine kinase AktAkt-dependent phosphorylationAberrant Akt activationEndothelial cellsKinase substrateKinase AktCell signalingPhosphorylation profilePhenotypic outcomesDownstream signalingAkt activationAkt1 phosphorylationHuman diseasesSystem-level analysisAKT1Vascular endothelial cellsRich resourcePhosphorylationSignalingGrowth factorAktCellsGenetic or therapeutic neutralization of ALK1 reduces LDL transcytosis and atherosclerosis in mice
Lee S, Schleer H, Park H, Jang E, Boyer M, Tao B, Gamez-Mendez A, Singh A, Folta-Stogniew E, Zhang X, Qin L, Xiao X, Xu L, Zhang J, Hu X, Pashos E, Tellides G, Shaul P, Lee W, Fernandez-Hernando C, Eichmann A, Sessa W. Genetic or therapeutic neutralization of ALK1 reduces LDL transcytosis and atherosclerosis in mice. Nature Cardiovascular Research 2023, 2: 438-448. PMID: 39196046, PMCID: PMC11358031, DOI: 10.1038/s44161-023-00266-2.Peer-Reviewed Original ResearchLDL transcytosisLDL receptor knockout miceReceptor knockout miceAtherosclerotic cardiovascular diseaseLow-density lipoprotein accumulationHigh-fat dietPromising therapeutic strategyTherapeutic neutralizationMacrophage infiltrationTriglyceride levelsLDL entryCardiovascular diseaseSelective monoclonal antibodiesLipoprotein accumulationTherapeutic strategiesKnockout micePlaque formationAtherosclerosis initiationType 1Genetic deletionArterial wallMonoclonal antibodiesEndothelial cellsLDL accumulationMice
2022
Inflammatory stress signaling via NF-kB alters accessible cholesterol to upregulate SREBP2 transcriptional activity in endothelial cells
Fowler JWM, Zhang R, Tao B, Boutagy NE, Sessa WC. Inflammatory stress signaling via NF-kB alters accessible cholesterol to upregulate SREBP2 transcriptional activity in endothelial cells. ELife 2022, 11: e79529. PMID: 35959888, PMCID: PMC9395194, DOI: 10.7554/elife.79529.Peer-Reviewed Original ResearchConceptsAcute inflammatory responseEndothelial cellsCholesterol homeostasisInflammatory stressInflammatory responsePro-inflammatory cytokinesSite of injuryCholesterol biosynthetic gene expressionNF-κB DNA bindingHuman endothelial cellsMultiple sclerosisInflammatory activationPrimary human endothelial cellsVascular endotheliumNF-κB-inducible genesTissue damageInducible targetAberrant activationRole of cholesterolSREBP2 activationMicrobial infectionsCholesterolKey transcription regulatorHomeostasisLeukocytes
2021
The loss of DHX15 impairs endothelial energy metabolism, lymphatic drainage and tumor metastasis in mice
Ribera J, Portolés I, Córdoba-Jover B, Rodríguez-Vita J, Casals G, González-de la Presa B, Graupera M, Solsona-Vilarrasa E, Garcia-Ruiz C, Fernández-Checa JC, Soria G, Tudela R, Esteve-Codina A, Espadas G, Sabidó E, Jiménez W, Sessa WC, Morales-Ruiz M. The loss of DHX15 impairs endothelial energy metabolism, lymphatic drainage and tumor metastasis in mice. Communications Biology 2021, 4: 1192. PMID: 34654883, PMCID: PMC8519955, DOI: 10.1038/s42003-021-02722-w.Peer-Reviewed Original ResearchConceptsKey cellular processesIntracellular ATP productionCellular processesZebrafish embryosDownstream substratesATP biosynthesisProteome analysisMitochondrial membraneEndothelial cellsDHX15ATP productionRegulatory functionsDifferential expressionComplex IVascular regulatory functionEnergy metabolismVascular biologyTumor metastasisTherapeutical targetGene deficiencyPrimary tumor growthLower oxygen consumptionVascular physiologyDownregulation of VEGFCellsEruptive xanthoma model reveals endothelial cells internalize and metabolize chylomicrons, leading to extravascular triglyceride accumulation
Cabodevilla AG, Tang S, Lee S, Mullick AE, Aleman JO, Hussain MM, Sessa WC, Abumrad NA, Goldberg IJ. Eruptive xanthoma model reveals endothelial cells internalize and metabolize chylomicrons, leading to extravascular triglyceride accumulation. Journal Of Clinical Investigation 2021, 131: e145800. PMID: 34128469, PMCID: PMC8203467, DOI: 10.1172/jci145800.Peer-Reviewed Original ResearchConceptsLPL-deficient miceScavenger receptor BISkin macrophagesEruptive xanthomasStudy of patientsLipid droplet biogenesisAccumulation of triglyceridesEndothelial cell barrierLipoprotein lipase hydrolysisChylomicron uptakeDroplet biogenesisReceptor BITG accumulationTissue uptakeTriglyceride accumulationDietary lipidsChylomicronsEndothelial cellsLipid accumulationAortic ECsLipid dropletsMacrophagesTriglyceridesHyperchylomicronemic patientsCultured ECsCharacterization of a Novel Caveolin Modulator That Reduces Vascular Permeability and Ocular Inflammation
Bernatchez PN, Tao B, Bradshaw RA, Eveleth D, Sessa WC. Characterization of a Novel Caveolin Modulator That Reduces Vascular Permeability and Ocular Inflammation. Translational Vision Science & Technology 2021, 10: 21-21. PMID: 34111267, PMCID: PMC8132009, DOI: 10.1167/tvst.10.6.21.Peer-Reviewed Original ResearchConceptsOcular inflammationCell-permeable peptideRetinal damageVascular permeabilityModel of uveitisVascular endothelial growth factorNitric oxide releaseEndothelial growth factorNovel cell-permeable peptideEndothelial cell signalingVascular leakageClinical developmentInflammationOxide releaseEndothelial cellsNO releaseGrowth factorUveitisVEGFDistinct assaysPhage display technologyPresent studyVivoCell signalingPeptides
2012
NogoB receptor is essential for extraembryonic vascular development and protein glycosylation
Park E, Sessa W. NogoB receptor is essential for extraembryonic vascular development and protein glycosylation. The FASEB Journal 2012, 26: 607.5-607.5. DOI: 10.1096/fasebj.26.1_supplement.607.5.Peer-Reviewed Original ResearchExtraembryonic vascular developmentDehydrodolichyl diphosphate synthaseProtein glycosylationPeri-implantation embryonic lethalityVascular developmentMutant yolk sacsProtein N-glycosylationYolk sacCKO embryosMutant embryosUseful model systemNon-functional formEmbryonic lethalityDiphosphate synthaseExtraembryonic tissuesN-glycosylationProtein stabilityEndothelial cellsConditional knockout miceDevelopment defectsTube formationMutantsCKO mouse modelModel systemEmbyronic developmentCharacterization of Lipid Droplet and Its Regulation by Caveolin‐1 in Endothelial Cells
Kuo A, Zhang X, Harrison K, Sessa W. Characterization of Lipid Droplet and Its Regulation by Caveolin‐1 in Endothelial Cells. The FASEB Journal 2012, 26: 597.1-597.1. DOI: 10.1096/fasebj.26.1_supplement.597.1.Peer-Reviewed Original ResearchDeficient endothelial cellsCav-1Lipid dropletsFatty acid uptakeLD formationCaveolin-1Putative hairpin structureSurface of LDsCav-1 null miceIntegral membrane proteinsCellular energy homeostasisPotential physiological functionsAcid uptakeEndothelial cellsLD homeostasisUnique organellesCaveolae microdomainsMembrane proteinsKey cell typesDiacylglycerol acyltransferasesNovel functionPlasma membraneBiological processesIntracellular regulationPhysiological functions
2007
Regulation of Caveolin‐2 Phosphorylation at Serines 23 and 36
Sowa G, Sessa W. Regulation of Caveolin‐2 Phosphorylation at Serines 23 and 36. The FASEB Journal 2007, 21: a1424-a1424. DOI: 10.1096/fasebj.21.6.a1424-b.Peer-Reviewed Original ResearchLipid rafts/caveolaeSerine 36 phosphorylationRafts/caveolaeSerine 23Cav-2Serine phosphorylationCav-1Phospho-specific antibodiesSubcellular fractionation dataSubcellular fractionation techniquesN-terminal serineEndothelial cellsCaveolar compartmentCaveolae assemblyLipid raftsSubcellular locationRegulated processSerine 36Caveolin-2Human endothelial cellsAdenoviral expressionIntracellular compartmentsPhosphorylationCaveolaeResidues 23
2001
Akt Down-regulation of p38 Signaling Provides a Novel Mechanism of Vascular Endothelial Growth Factor-mediated Cytoprotection in Endothelial Cells*
Gratton J, Morales-Ruiz M, Kureishi Y, Fulton D, Walsh K, Sessa W. Akt Down-regulation of p38 Signaling Provides a Novel Mechanism of Vascular Endothelial Growth Factor-mediated Cytoprotection in Endothelial Cells*. Journal Of Biological Chemistry 2001, 276: 30359-30365. PMID: 11387313, DOI: 10.1074/jbc.m009698200.Peer-Reviewed Original ResearchMeSH KeywordsAdenoviridaeAnimalsApoptosisBlotting, WesternCattleCell DeathCell LineCell SurvivalCells, CulturedDose-Response Relationship, DrugDown-RegulationEndothelial Growth FactorsEndothelium, VascularEnzyme ActivationEnzyme InhibitorsFlow CytometryHumansImidazolesLymphokinesMitogen-Activated Protein KinasesP38 Mitogen-Activated Protein KinasesPhosphatidylinositol 3-KinasesPhosphorylationProtein BindingProtein Serine-Threonine KinasesProto-Oncogene ProteinsProto-Oncogene Proteins c-aktPyridinesSignal TransductionTime FactorsUmbilical VeinsVascular Endothelial Growth Factor AVascular Endothelial Growth FactorsConceptsMEKK3 phosphorylationP38 activationMEKK3 kinase activityMitogen-activated protein kinaseP38 mitogen-activated protein kinaseP38-dependent apoptosisP38 MAPK inhibitor SB203580Dominant-negative RacInhibition of PIActivation of MKK3/6Vascular endothelial growth factorMAPK inhibitor SB203580P38 MAPK pathwayP38 MAPK activationEndothelial cellsEndothelial cell survivalGrowth factorRac activationProtein kinaseActive AktPro-apoptotic effectsKinase activityInhibitor SB203580MAPK activationP38 signalingHeat Shock Protein 90 Mediates the Balance of Nitric Oxide and Superoxide Anion from Endothelial Nitric-oxide Synthase*
Pritchard K, Ackerman A, Gross E, Stepp D, Shi Y, Fontana J, Baker J, Sessa W. Heat Shock Protein 90 Mediates the Balance of Nitric Oxide and Superoxide Anion from Endothelial Nitric-oxide Synthase*. Journal Of Biological Chemistry 2001, 276: 17621-17624. PMID: 11278264, DOI: 10.1074/jbc.c100084200.Peer-Reviewed Original ResearchConceptsEndothelial nitric oxide synthaseBovine coronary endothelial cellsNitric oxide synthaseHeat shock protein 90Shock protein 90Nitric oxidePhospho-eNOS levelsCoronary endothelial cellsProtein 90ENOS activityAssociation of hsp90Calcium ionophoreEndothelial cellsNitrite productionVascular biologySuperoxide anionAssociationPretreatmentHsp90SynthaseSphingosine 1-Phosphate Activates Akt, Nitric Oxide Production, and Chemotaxis through a GiProtein/Phosphoinositide 3-Kinase Pathway in Endothelial Cells*
Morales-Ruiz M, Lee M, Zöllner S, Gratton J, Scotland R, Shiojima I, Walsh K, Hla T, Sessa W. Sphingosine 1-Phosphate Activates Akt, Nitric Oxide Production, and Chemotaxis through a GiProtein/Phosphoinositide 3-Kinase Pathway in Endothelial Cells*. Journal Of Biological Chemistry 2001, 276: 19672-19677. PMID: 11278592, DOI: 10.1074/jbc.m009993200.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlotting, NorthernBlotting, WesternCattleCell MovementChemotaxisCulture Media, Serum-FreeDose-Response Relationship, DrugEndothelial Growth FactorsEndothelium, VascularEnzyme ActivationGenes, DominantGTP-Binding Protein alpha Subunits, Gi-GoLungLymphokinesLysophospholipidsNeovascularization, PhysiologicNitric OxideNitric Oxide SynthaseNitric Oxide Synthase Type IIIPhosphatidylinositol 3-KinasesPhosphorylationProtein BindingProtein Serine-Threonine KinasesProto-Oncogene ProteinsProto-Oncogene Proteins c-aktReceptors, Cell SurfaceSignal TransductionSphingosineTime FactorsVascular Endothelial Growth Factor AVascular Endothelial Growth FactorsVirulence Factors, BordetellaConceptsEndothelial differentiation gene familySerine/threonine kinase AktHeterotrimeric G proteinsThreonine kinase AktEDG-1 receptorGene familyAkt substrateKinase AktEndothelial cell chemotaxisActivates AktENOS phosphorylationAkt activationG proteinsCell survivalEndothelial nitric oxide synthasePhosphorylationAktCell chemotaxisSppSignalingGrowth factorVascular endothelial growth factorChemotaxisEndothelial cellsSphingosine
2000
In vivo delivery of the caveolin-1 scaffolding domain inhibits nitric oxide synthesis and reduces inflammation
Bucci M, Gratton J, Rudic R, Acevedo L, Roviezzo F, Cirino G, Sessa W. In vivo delivery of the caveolin-1 scaffolding domain inhibits nitric oxide synthesis and reduces inflammation. Nature Medicine 2000, 6: 1362-1367. PMID: 11100121, DOI: 10.1038/82176.Peer-Reviewed Original ResearchConceptsCaveolin-1Signal transductionSmall-molecule mimicryCaveolae assemblyInternalization sequenceCoat proteinEndothelial cellsPhysiological importanceEndothelial nitric oxide synthase (eNOS) inhibitorTransductionCholesterol transportNitric oxide synthase inhibitorChimeric peptideInhibits nitric oxide synthesisOxide synthase inhibitorNitric oxide synthesisNew therapeutic approachesNitric oxide productionSelective inhibitionDomainPeptidesCaveolinAcute inflammationCellsSystemic administrationThe HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals.
Kureishi Y, Luo Z, Shiojima I, Bialik A, Fulton D, Lefer D, Sessa W, Walsh K. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nature Medicine 2000, 6: 1004-1010. PMID: 10973320, PMCID: PMC2828689, DOI: 10.1038/79510.Peer-Reviewed Original ResearchConceptsProtein kinase Akt/PKBKinase Akt/PKBProtein kinase AktAkt/PKBAkt-dependent mannerVascular structure formationActivation of AktKinase AktVascular endothelial growth factor treatmentEnhanced phosphorylationBlood vessel growthNew blood vessel growthAktGrowth factor treatmentVessel growthEndothelial cellsEndothelial nitric oxide synthaseRecent studiesHMG-CoA reductase inhibitor simvastatinAngiogenesisPKBFactor treatmentPhosphorylationReductase inhibitor simvastatinApoptosisReconstitution of an Endothelial Nitric-oxide Synthase (eNOS), hsp90, and Caveolin-1 Complex in Vitro EVIDENCE THAT hsp90 FACILITATES CALMODULIN STIMULATED DISPLACEMENT OF eNOS FROM CAVEOLIN-1*
Gratton J, Fontana J, O'Connor D, Garcı́a-Cardeña G, McCabe T, Sessa W. Reconstitution of an Endothelial Nitric-oxide Synthase (eNOS), hsp90, and Caveolin-1 Complex in Vitro EVIDENCE THAT hsp90 FACILITATES CALMODULIN STIMULATED DISPLACEMENT OF eNOS FROM CAVEOLIN-1*. Journal Of Biological Chemistry 2000, 275: 22268-22272. PMID: 10781589, DOI: 10.1074/jbc.m001644200.Peer-Reviewed Original ResearchConceptsEndothelial nitric oxide synthaseAssociation of eNOSNitric oxide synthaseLung microvascular endothelial cellsCaveolin-1Microvascular endothelial cellsENOS enzymatic activityAction of CaMBovine lung microvascular endothelial cellsENOS functionCalcium-activated calmodulinConcentration of CaMShock protein 90Addition of CaMEndothelial cellsVitro EvidenceCav-1Protein 90AssociationPresence of Hsp90Vascular Endothelial Growth Factor–Stimulated Actin Reorganization and Migration of Endothelial Cells Is Regulated via the Serine/Threonine Kinase Akt
Morales-Ruiz M, Fulton D, Sowa G, Languino L, Fujio Y, Walsh K, Sessa W. Vascular Endothelial Growth Factor–Stimulated Actin Reorganization and Migration of Endothelial Cells Is Regulated via the Serine/Threonine Kinase Akt. Circulation Research 2000, 86: 892-896. PMID: 10785512, DOI: 10.1161/01.res.86.8.892.Peer-Reviewed Original ResearchConceptsSignal transduction mechanismsCell migrationActin reorganizationActive AktMyr-AktSerine/threonine kinase AktCell signal transduction mechanismsTransduction mechanismsThreonine kinase AktVascular endothelial growth factorDominant-negative AktDistinct signal transduction mechanismsBovine lung microvascular endothelial cellsEndothelial cellsAbsence of VEGFActin cytoskeletonGrowth factorMicrovascular endothelial cellsKinase AktActin rearrangementStress fibersF-actinCell locomotionEndothelial growth factorEndothelial cell proliferation