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 channelMYH9
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 VEGFCellsDefective 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 ECs
2015
Endothelial Glucocorticoid Receptor Suppresses Atherogenesis—Brief Report
Goodwin JE, Zhang X, Rotllan N, Feng Y, Zhou H, Fernández-Hernando C, Yu J, Sessa WC. Endothelial Glucocorticoid Receptor Suppresses Atherogenesis—Brief Report. Arteriosclerosis Thrombosis And Vascular Biology 2015, 35: 779-782. PMID: 25810297, PMCID: PMC4375730, DOI: 10.1161/atvbaha.114.304525.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAortaAortic DiseasesApolipoproteins EAtherosclerosisBody WeightBrachiocephalic TrunkCholesterolDiet, High-FatDisease Models, AnimalEndothelial CellsGenotypeMacrophagesMice, Inbred C57BLMice, KnockoutPhenotypeReceptors, GlucocorticoidSeverity of Illness IndexTime FactorsTriglyceridesConceptsEndothelial glucocorticoid receptorGlucocorticoid receptorHigh-fat diet feedingApoE knockout backgroundSevere atherosclerotic lesionsGroups of micePathogenesis of atherosclerosisAortic sinusTotal cholesterolAtherosclerosis progressionBrachiocephalic arteryControl miceInflammatory milieuTonic inhibitionDiet feedingMacrophage recruitmentAtherosclerotic lesionsBody weightMiceKnockout backgroundReceptorsLesionsAtherosclerosisInflammationArtery
2010
Telmisartan regresses left ventricular hypertrophy in caveolin-1-deficient mice
Kreiger M, Di Lorenzo A, Teutsch C, Kauser K, Sessa WC. Telmisartan regresses left ventricular hypertrophy in caveolin-1-deficient mice. Laboratory Investigation 2010, 90: 1573-1581. PMID: 20585312, PMCID: PMC3248785, DOI: 10.1038/labinvest.2010.116.Peer-Reviewed Original ResearchConceptsCav-1 KO miceAngiotensin receptor blockersKO miceCardiac functionLV hypertrophyWT miceCardiac hypertrophyΒ-myosin heavy chainBody weight ratioTibial length ratioNatriuretic peptide ACaveolin-1-deficient miceCav-1 KOReceptor blockersPerivascular fibrosisVentricular hypertrophyVentricular weightAngiotensin IIIntramyocardial vesselsSpontaneous modelUnique genetic modelHypertrophyMiceTreatmentCaveolin-1
2004
Antiangiogenic therapy Creating a unique “window” of opportunity
Lin M, Sessa W. Antiangiogenic therapy Creating a unique “window” of opportunity. Cancer Cell 2004, 6: 529-531. PMID: 15607955, DOI: 10.1016/j.ccr.2004.12.003.Peer-Reviewed Original ResearchAngiogenesis InhibitorsAngiopoietin-1AnimalsAntibodies, MonoclonalBasement MembraneBlood VesselsCell MovementCollagenasesCombined Modality TherapyGamma RaysGliomaHumansMiceModels, BiologicalNeoplasmsNeovascularization, PathologicPericytesReceptor, TIE-2Time FactorsVascular Endothelial Growth Factor Receptor-2Xenograft Model Antitumor Assays
2001
Distinction between signaling mechanisms in lipid rafts vs. caveolae
Sowa G, Pypaert M, Sessa W. Distinction between signaling mechanisms in lipid rafts vs. caveolae. Proceedings Of The National Academy Of Sciences Of The United States Of America 2001, 98: 14072-14077. PMID: 11707586, PMCID: PMC61169, DOI: 10.1073/pnas.241409998.Peer-Reviewed Original ResearchConceptsCav-1Raft domainsLipid raftsCholesterol-rich lipid raft domainsLipid raft domainsCaveolae assemblyEndothelial nitric oxide synthaseCaveolae biogenesisAcylated proteinsSignal transductionSpatial regulationPlasma membraneNegative regulationCaveolin-1CaveolaeFirst clear exampleRaftsPhysical interactionProteinCellsRegulationENOS functionBiogenesisDomainClear exampleAkt-Mediated Phosphorylation of the G Protein-Coupled Receptor EDG-1 Is Required for Endothelial Cell Chemotaxis
Lee M, Thangada S, Paik J, Sapkota G, Ancellin N, Chae S, Wu M, Morales-Ruiz M, Sessa W, Alessi D, Hla T. Akt-Mediated Phosphorylation of the G Protein-Coupled Receptor EDG-1 Is Required for Endothelial Cell Chemotaxis. Molecular Cell 2001, 8: 693-704. PMID: 11583630, DOI: 10.1016/s1097-2765(01)00324-0.Peer-Reviewed Original ResearchMeSH KeywordsActinsAnimalsCell LineChemotaxisEndothelium, VascularEnzyme ActivationHumansImmediate-Early ProteinsLysophospholipidsModels, BiologicalNeovascularization, PhysiologicPhosphorylationProtein BindingProtein Serine-Threonine KinasesProtein Structure, TertiaryProto-Oncogene ProteinsProto-Oncogene Proteins c-aktRac GTP-Binding ProteinsReceptors, Cell SurfaceReceptors, G-Protein-CoupledReceptors, LysophospholipidRecombinant Fusion ProteinsSignal TransductionSphingosineConceptsG protein-coupled receptor Edg-1EDG-1Cell migrationRac activationAkt-Mediated PhosphorylationCortical actin assemblyProtein kinase AktThird intracellular loopAkt bindsActin assemblyEndothelial cell migrationKinase AktSpecificity switchEndothelial cell chemotaxisCellular phenomenaDependent signalingIntracellular loopAktCell chemotaxisTransactivationPhosphorylationGPCRsChemotaxisActivationMutantsAkt 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 signalingCan modulation of endothelial nitric oxide synthase explain the vasculoprotective actions of statins?
Sessa W. Can modulation of endothelial nitric oxide synthase explain the vasculoprotective actions of statins? Trends In Molecular Medicine 2001, 7: 189-191. PMID: 11325618, DOI: 10.1016/s1471-4914(01)01985-2.Peer-Reviewed Original ResearchConceptsEndothelial nitric oxide synthaseMainstay of therapyCoronary artery diseaseLipid-lowering effectsNitric oxide synthaseNitric oxide synthesisClass of drugsNitric oxide releaseArtery diseaseVasculoprotective actionsOxide synthaseBeneficial actionsOxide synthesisOxide releaseCellular mechanismsStatinsDrugsRecent insightsTherapyMainstayDiseaseHeat 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 cellsSphingosineThe Sonic Hedgehog Receptor Patched Associates with Caveolin-1 in Cholesterol-rich Microdomains of the Plasma Membrane* 210
Karpen H, Bukowski J, Hughes T, Gratton J, Sessa W, Gailani M. The Sonic Hedgehog Receptor Patched Associates with Caveolin-1 in Cholesterol-rich Microdomains of the Plasma Membrane* 210. Journal Of Biological Chemistry 2001, 276: 19503-19511. PMID: 11278759, DOI: 10.1074/jbc.m010832200.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsBinding SitesBlotting, WesternCaveolin 1CaveolinsCell MembraneCholesterolCOS CellsDNA, ComplementaryDrosophila ProteinsElectrophoresis, Polyacrylamide GelGlutathione TransferaseHumansImmunohistochemistryMembrane MicrodomainsMembrane ProteinsMicroscopy, ConfocalModels, BiologicalMolecular Sequence DataMutationPatched ReceptorsPrecipitin TestsProtein BindingProtein Structure, TertiaryProtein TransportReceptors, Cell SurfaceReceptors, G-Protein-CoupledRecombinant Fusion ProteinsSignal TransductionSmoothened ReceptorSubcellular FractionsTime FactorsConceptsCholesterol-rich microdomainsRaft microdomainsCaveolin-1Receptor complexEarly embryonic patterningFractionation studiesHedgehog receptor complexCaveolin-enriched microdomainsBuoyant density fractionsEmbryonic patterningHh proteinsLipid raftsSubcellular localizationPlasma membranePatchedPlasmalemmal cholesterolProtein experimentsImmunoprecipitation studiesSmoothenedMicrodomainsConfocal microscopyImmunocytochemistry dataComplexesMembraneDrosophila
2000
Direct Interaction between Endothelial Nitric-oxide Synthase and Dynamin-2 IMPLICATIONS FOR NITRIC-OXIDE SYNTHASE FUNCTION*
Cao S, Yao J, McCabe T, Yao Q, Katusic Z, Sessa W, Shah V. Direct Interaction between Endothelial Nitric-oxide Synthase and Dynamin-2 IMPLICATIONS FOR NITRIC-OXIDE SYNTHASE FUNCTION*. Journal Of Biological Chemistry 2000, 276: 14249-14256. PMID: 11120737, DOI: 10.1074/jbc.m006258200.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAortaBlotting, WesternCalcimycinCattleCell LineDose-Response Relationship, DrugDynamin IDynaminsEndothelium, VascularGlutathione TransferaseGolgi ApparatusGTP PhosphohydrolasesIonophoresKineticsMicroscopy, ConfocalMicroscopy, FluorescenceNitric Oxide SynthaseNitric Oxide Synthase Type IIIPrecipitin TestsProtein BindingProtein BiosynthesisRatsRecombinant Fusion ProteinsTransfectionConceptsDynamin 2Bovine aortic endothelial cellsRecombinant eNOS proteinDirect protein-protein interactionDouble-label confocal immunofluorescenceProtein-protein interactionsSpecific protein interactionsDirect interactionClone 9 cellsEndothelial nitric oxide synthaseMembrane compartmentsLarge GTPaseGlutathione S-transferaseProtein interactionsNovel functionDynaminECV-304 cellsSynthase functionIntracellular signalsMembrane distributionConfocal immunofluorescenceFluorescent proteinENOS regulationGreen fluorescentProteinIn 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 administrationSimvastatin upregulates coronary vascular endothelial nitric oxide production in conscious dogs
Mital S, Zhang X, Zhao G, Bernstein R, Smith C, Fulton D, Sessa W, Liao J, Hintze T. Simvastatin upregulates coronary vascular endothelial nitric oxide production in conscious dogs. AJP Heart And Circulatory Physiology 2000, 279: h2649-h2657. PMID: 11087217, DOI: 10.1152/ajpheart.2000.279.6.h2649.Peer-Reviewed Original ResearchMeSH KeywordsAcetylcholineAdenosineAnimalsAnticholesteremic AgentsConsciousnessCoronary CirculationDogsEndothelium, VascularEnzyme InhibitorsGene Expression Regulation, EnzymologicHeart RateIn Vitro TechniquesMicrocirculationMyocardiumNG-Nitroarginine Methyl EsterNitric OxideNitric Oxide SynthaseNitric Oxide Synthase Type IIINitritesNitroglycerinOxygen ConsumptionRNA, MessengerSimvastatinVasodilationVasodilator AgentsVeratrineConceptsEndothelial nitric oxide synthaseCoronary blood flowCoronary vasodilationConscious dogsSimvastatin administrationVascular endothelial nitric oxide productionVascular endothelial nitric oxide synthaseNO productionEndothelial nitric oxide productionEndothelium-independent vasodilatorCoronary vascular endotheliumShort-term administrationLipid-lowering effectsNitric oxide synthaseEndothelial NO productionMyocardial oxygen consumptionNitric oxide productionNO-dependent regulationPlasma nitrateGeneral anesthesiaENOS proteinCoronary microvesselsOxide synthaseMongrel dogsENOS mRNAGeldanamycin, an inhibitor of heat shock protein 90 (Hsp90) mediated signal transduction has anti‐inflammatory effects and interacts with glucocorticoid receptor in vivo
Bucci M, Roviezzo F, Cicala C, Sessa W, Cirino G. Geldanamycin, an inhibitor of heat shock protein 90 (Hsp90) mediated signal transduction has anti‐inflammatory effects and interacts with glucocorticoid receptor in vivo. British Journal Of Pharmacology 2000, 131: 13-16. PMID: 10960063, PMCID: PMC1572305, DOI: 10.1038/sj.bjp.0703549.Peer-Reviewed Original ResearchConceptsAnti-inflammatory effectsAnti-inflammatory actionEdema formationRU 486Heat shock protein 90Shock protein 90Endothelial nitric oxide synthaseEndothelium-dependent relaxationAnti-inflammatory dosePotential anti-inflammatory drugsVascular endothelial growth factorNitric oxide synthaseAnti-inflammatory drugsEndothelial growth factorDose-dependent mannerProtein 90Specific inhibitorIntact blood vesselsIntraplantar administrationPaw edemaMiddle arteryOxide synthaseRat aortaTherapeutic rationaleGlucocorticoid receptorThe 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 simvastatinApoptosis