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 systemSelective inhibition of tumor microvascular permeability by cavtratin blocks tumor progression in mice
Gratton J, Lin M, Yu J, Weiss E, Jiang Z, Fairchild T, Iwakiri Y, Groszmann R, Claffey K, Cheng Y, Sessa W. Selective inhibition of tumor microvascular permeability by cavtratin blocks tumor progression in mice. Cancer Cell 2024, 42: 1127. PMID: 38821059, DOI: 10.1016/j.ccell.2024.05.009.Peer-Reviewed Original ResearchZFYVE21 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 donorDynamic metabolism of endothelial triglycerides protects against atherosclerosis in mice
Boutagy N, Gamez-Mendez A, Fowler J, Zhang H, Chaube B, Esplugues E, Kuo A, Lee S, Horikami D, Zhang J, Citrin K, Singh A, Coon B, Lee M, Suarez Y, Fernandez-Hernando C, Sessa W. Dynamic metabolism of endothelial triglycerides protects against atherosclerosis in mice. Journal Of Clinical Investigation 2024, 134: e170453. PMID: 38175710, PMCID: PMC10866653, DOI: 10.1172/jci170453.Peer-Reviewed Original Research
2023
Endothelial nitric oxide synthase (eNOS) S1176 phosphorylation status governs atherosclerotic lesion formation
Nguyen T, Rahman N, Sessa W, Lee M. Endothelial nitric oxide synthase (eNOS) S1176 phosphorylation status governs atherosclerotic lesion formation. Frontiers In Cardiovascular Medicine 2023, 10: 1279868. PMID: 38034389, PMCID: PMC10683645, DOI: 10.3389/fcvm.2023.1279868.Peer-Reviewed Original ResearchAtherosclerotic plaque formationPlaque formationAkt1 null miceSingle amino acid substitutionMutant miceLesion formationImportance of AktUnique expression patternGene expression analysisIndex of atherosclerosisFavorable lipid profileVascular protective roleAtherosclerotic lesion formationAthero-protective effectsEndothelial NO generationAmino acid substitutionsDouble knockout miceDeletion backgroundPhosphorylation sitesAspartate substitutionPhosphorylation statusExpression analysisEnzyme functionExpression patternsENOS deletionTNFα 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 factorAktCellsAcetate 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 ResearchConceptsTGF-β signalingChronic vascular diseaseTGF-β receptor ALK5Mesenchymal transitionInduction of EndMTVascular diseaseMolecular basisPositive feedback loopReceptor ALK5Cellular levelSMADs 2Novel targetEndMT inductionMetabolic modulationMetabolic basisFibrotic stateSignalingPotential treatmentEndMTTGFDiseaseActivationInductionACSS2PDK4Genetic 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 accumulationMiceGenetic or therapeutic neutralization of ALK1 reduces LDL transcytosis and atherosclerosis in mice
Lee, S., Schleer, H., Park, H. et al. Genetic or therapeutic neutralization of ALK1 reduces LDL transcytosis and atherosclerosis in mice. Nat Cardiovasc Res 2, 438–448 (2023). https://doi.org/10.1038/s44161-023-00266-2Peer-Reviewed Original Research
2022
Macrophage-Derived 25-Hydroxycholesterol Promotes Vascular Inflammation, Atherogenesis, and Lesion Remodeling
Canfrán-Duque A, Rotllan N, Zhang X, Andrés-Blasco I, Thompson B, Sun J, Price N, Fernández-Fuertes M, Fowler J, Gómez-Coronado D, Sessa W, Giannarelli C, Schneider R, Tellides G, McDonald J, Fernández-Hernando C, Suárez Y. Macrophage-Derived 25-Hydroxycholesterol Promotes Vascular Inflammation, Atherogenesis, and Lesion Remodeling. Circulation 2022, 147: 388-408. PMID: 36416142, PMCID: PMC9892282, DOI: 10.1161/circulationaha.122.059062.Peer-Reviewed Original ResearchConceptsLipid-loaded macrophagesLineage-tracing mouse modelsSREBP transcriptional activityCholesterol biosynthetic intermediatesWestern diet feedingAccessible cholesterolDifferent macrophage populationsTranscriptomic analysisKey immune regulatorsPlasma membraneAtherosclerosis progressionImmune activationTranscriptional activityGene expressionDiet feedingInflammatory responseMouse bone marrowLiver X receptorBiosynthetic intermediatesSterol metabolismApoptosis susceptibilityToll-like receptor 4Proinflammatory gene expressionHuman coronary atherosclerotic lesionsMouse atherosclerotic plaquesMolecular determinants of peri‐apical targeting of inositol 1,4,5‐trisphosphate receptor type 3 in cholangiocytes
Rodrigues MA, Gomes DA, Fiorotto R, Guerra MT, Weerachayaphorn J, Bo T, Sessa WC, Strazzabosco M, Nathanson MH. Molecular determinants of peri‐apical targeting of inositol 1,4,5‐trisphosphate receptor type 3 in cholangiocytes. Hepatology Communications 2022, 6: 2748-2764. PMID: 35852334, PMCID: PMC9512452, DOI: 10.1002/hep4.2042.Peer-Reviewed Original ResearchConceptsLipid raftsCaveolin-1Intact lipid raftsType 3 inositol trisphosphate receptorApical regionC-terminal amino acidsTrisphosphate receptor type 3Madin-Darby canine kidney cellsCanine kidney cellsFluorescence microscopy techniquesInositol trisphosphate receptorApical localizationTrisphosphate receptorHeavy chain 9Molecular determinantsChemical disruptionAmino acidsITPR3RaftsKidney cellsIntracellular CaFinal common eventReceptor type 3Release channelMYH9Inflammatory 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 regulatorHomeostasisLeukocytesTargeting the vasculature in cardiometabolic disease
Boutagy NE, Singh AK, Sessa WC. Targeting the vasculature in cardiometabolic disease. Journal Of Clinical Investigation 2022, 132: e148556. PMID: 35289308, PMCID: PMC8920329, DOI: 10.1172/jci148556.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsCardiometabolic diseasesCardiometabolic disease burdenOptimal medical therapyType 2 diabetesContext of atherosclerosisCardiometabolic changesCV morbidityEndothelial dysfunctionEjection fractionGlycemic controlHeart failureMedical therapyProinflammatory mediatorsVascular inflammationDisease burdenDisease progressionCardiovascular diseaseVascular remodelingPathological changesEpidemic proportionsVascular endotheliumMetabolic diseasesDiseaseVasculatureObesity
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 VEGFCellsDe novo DHDDS variants cause a neurodevelopmental and neurodegenerative disorder with myoclonus
Galosi S, Edani BH, Martinelli S, Hansikova H, Eklund EA, Caputi C, Masuelli L, Corsten-Janssen N, Srour M, Oegema R, Bosch DGM, Ellis CA, Amlie-Wolf L, Accogli A, Atallah I, Averdunk L, Barañano KW, Bei R, Bagnasco I, Brusco A, Demarest S, Alaix AS, Di Bonaventura C, Distelmaier F, Elmslie F, Gan-Or Z, Good JM, Gripp K, Kamsteeg EJ, Macnamara E, Marcelis C, Mercier N, Peeden J, Pizzi S, Pannone L, Shinawi M, Toro C, Verbeek NE, Venkateswaran S, Wheeler PG, Zdrazilova L, Zhang R, Zorzi G, Guerrini R, Sessa WC, Lefeber DJ, Tartaglia M, Hamdan FF, Grabińska KA, Leuzzi V. De novo DHDDS variants cause a neurodevelopmental and neurodegenerative disorder with myoclonus. Brain 2021, 145: 208-223. PMID: 34382076, PMCID: PMC8967098, DOI: 10.1093/brain/awab299.Peer-Reviewed Original ResearchConceptsRetinitis pigmentosaNeurodegenerative disordersMovement disordersDe novo pathogenic variantsHypokinetic movement disordersCongenital disorderLong-term outcomesNeurodevelopmental disordersNovo pathogenic variantsNeuronal ceroid lipofuscinosisProgressive myoclonus epilepsyDisease courseNeurological declineClinical featuresProgressive encephalopathyPsychiatric disturbancesMyelinated fibersLarge cohortCortical tremorCognitive deteriorationDisease-causing variantsEndosomal-lysosomal pathwayAutosomal recessive formPathogenic variantsAltered lysosomesDefective 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 translocationEruptive 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