2024
Endothelial γ-protocadherins inhibit KLF2 and KLF4 to promote atherosclerosis
Joshi D, Coon B, Chakraborty R, Deng H, Yang Z, Babar M, Fernandez-Tussy P, Meredith E, Attanasio J, Joshi N, Traylor J, Orr A, Fernandez-Hernando C, Libreros S, Schwartz M. Endothelial γ-protocadherins inhibit KLF2 and KLF4 to promote atherosclerosis. Nature Cardiovascular Research 2024, 3: 1035-1048. PMID: 39232138, PMCID: PMC11399086, DOI: 10.1038/s44161-024-00522-z.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAtherosclerosisCadherin Related ProteinsCadherinsDisease Models, AnimalEndothelial CellsHuman Umbilical Vein Endothelial CellsHumansKruppel-Like Factor 4Kruppel-Like Transcription FactorsMaleMiceMice, Inbred C57BLMice, KnockoutPlaque, AtheroscleroticReceptors, NotchSignal TransductionConceptsAtherosclerotic cardiovascular diseaseIntracellular domainNotch intracellular domainTranscription factor KLF2Mechanisms of vascular inflammationAnti-inflammatory programVascular endothelial cellsHost defenseCleavage resultsAntibody blockadeGenetic deletionVascular inflammationViral infectionImmune systemEndothelial cellsCardiovascular diseasePromote atherosclerosisBlood flowKLF2KLF4Suppressive signalsEndotheliumMechanistic studies
2022
mTOR inhibition prevents angiotensin II–induced aortic rupture and pseudoaneurysm but promotes dissection in Apoe-deficient mice
He C, Jiang B, Wang M, Ren P, Murtada SI, Caulk AW, Li G, Qin L, Assi R, Lovoulos CJ, Schwartz MA, Humphrey JD, Tellides G. mTOR inhibition prevents angiotensin II–induced aortic rupture and pseudoaneurysm but promotes dissection in Apoe-deficient mice. JCI Insight 2022, 7: e155815. PMID: 35132962, PMCID: PMC8855820, DOI: 10.1172/jci.insight.155815.Peer-Reviewed Original ResearchConceptsApoE-deficient miceAngiotensin IIVascular wall cellsAortic tearAortic ruptureMTOR inhibitionSmooth muscle cell hypertrophyMatricellular proteinWall cellsSuprarenal abdominal aortaMuscle cell hypertrophyExtracellular matrix accumulationInhibition of mTORRole of mTORSubadventitial hematomaFree ruptureAortic dissectionAortic diseaseAortic aneurysmSignificant dissectionAbdominal aortaHemorrhagic lesionsExtensive dissectionMetalloproteinase expressionCell hypertrophy
2019
ARHGAP18: A Flow‐Responsive Gene That Regulates Endothelial Cell Alignment and Protects Against Atherosclerosis
Lay AJ, Coleman PR, Formaz‐Preston A, Ting KK, Roediger B, Weninger W, Schwartz MA, Vadas MA, Gamble JR. ARHGAP18: A Flow‐Responsive Gene That Regulates Endothelial Cell Alignment and Protects Against Atherosclerosis. Journal Of The American Heart Association 2019, 8: e010057. PMID: 30630384, PMCID: PMC6497359, DOI: 10.1161/jaha.118.010057.Peer-Reviewed Original ResearchConceptsApolipoprotein EHigh-fat diet-induced modelIntercellular adhesion molecule-1Endothelial nitric oxide synthaseHigh-fat dietDevelopment of atherosclerosisNitric oxide synthaseDiet-induced modelAdhesion molecule-1Double mutant miceAortic diseaseAtherosclerosis developmentInflammatory phenotypeOxide synthaseMolecule-1AtherosclerosisEarly onsetProtective genesMiceFlow-responsive genesAtheroprotective regionsEndothelial cell alignmentAdaptive responseAnalysis of ECEC ability
2018
Inhibiting Integrin α5 Cytoplasmic Domain Signaling Reduces Atherosclerosis and Promotes Arteriogenesis
Budatha M, Zhang J, Zhuang ZW, Yun S, Dahlman JE, Anderson DG, Schwartz MA. Inhibiting Integrin α5 Cytoplasmic Domain Signaling Reduces Atherosclerosis and Promotes Arteriogenesis. Journal Of The American Heart Association 2018, 7: e007501. PMID: 29382667, PMCID: PMC5850249, DOI: 10.1161/jaha.117.007501.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAortaAortic DiseasesAtherosclerosisCyclic Nucleotide Phosphodiesterases, Type 4Disease Models, AnimalExtracellular MatrixFibronectinsFibrosisGenetic Predisposition to DiseaseHindlimbInflammation MediatorsIntegrin alpha2Integrin alpha5IschemiaLeukocytesMaleMatrix MetalloproteinasesMice, Inbred C57BLMice, Knockout, ApoEMuscle, SkeletalNeovascularization, PhysiologicNF-kappa BPhenotypePlaque, AtheroscleroticSignal TransductionVascular RemodelingConceptsEndothelial inflammatory activationAtherosclerotic plaque sizeInflammatory activationPlaque stabilityVascular remodelingEndothelial NF-κB activationSmooth muscle cell contentPlaque sizeFemoral artery ligationMuscle cell contentTreatment of atherosclerosisInflammatory gene expressionPotential therapeutic targetFibrous cap thicknessNF-κB activationSmaller atherosclerotic plaquesArtery ligationAortic rootHindlimb ischemiaCompensatory remodelingAtherosclerotic plaquesTherapeutic targetLeukocyte contentMetalloproteinase expressionEndothelial basement membrane
2015
KLF4 is a key determinant in the development and progression of cerebral cavernous malformations
Cuttano R, Rudini N, Bravi L, Corada M, Giampietro C, Papa E, Morini MF, Maddaluno L, Baeyens N, Adams RH, Jain MK, Owens GK, Schwartz M, Lampugnani MG, Dejana E. KLF4 is a key determinant in the development and progression of cerebral cavernous malformations. EMBO Molecular Medicine 2015, 8: 6-24. PMID: 26612856, PMCID: PMC4718159, DOI: 10.15252/emmm.201505433.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBone Morphogenetic Protein 6Cell ProliferationDisease Models, AnimalDisease ProgressionEndothelial CellsHEK293 CellsHemangioma, Cavernous, Central Nervous SystemHumansKRIT1 ProteinKruppel-Like Factor 4Kruppel-Like Transcription FactorsMiceMice, Inbred C57BLMice, KnockoutMicrotubule-Associated ProteinsMitogen-Activated Protein Kinase 7MutationProto-Oncogene ProteinsRNA InterferenceSignal TransductionSmad1 ProteinTransforming Growth Factor betaConceptsKruppel-like factor 4Cerebral cavernous malformationsEndothelial cellsCavernous malformationsFamilial cerebral cavernous malformationsCentral nervous systemDouble knockout miceGrowth factor-beta/bone morphogenetic protein signalingCerebral hemorrhageMouse mortalityPharmacological treatmentCurrent therapiesVascular malformationsKnockout miceTherapeutic targetNervous systemMesenchymal transitionKLF4 transcriptional activityMalformationsCCM3 genesFactor 4Function mutationsEndMTMorphogenetic protein signalingBone morphogenetic protein (BMP) signaling
2012
Endothelial 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 factorThe role of p21-activated kinase in the initiation of atherosclerosis
Jhaveri K, Debnath P, Chernoff J, Sanders J, Schwartz M. The role of p21-activated kinase in the initiation of atherosclerosis. BMC Cardiovascular Disorders 2012, 12: 55. PMID: 22824149, PMCID: PMC3489605, DOI: 10.1186/1471-2261-12-55.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAorta, ThoracicAortic DiseasesAtherosclerosisBiomechanical PhenomenaCells, CulturedDisease Models, AnimalEndothelial CellsFibronectinsGalectin 3ImmunohistochemistryInflammation MediatorsIntercellular Adhesion Molecule-1MaleMiceMice, Inbred C57BLMice, KnockoutP21-Activated KinasesRegional Blood FlowTranscription Factor RelBVascular Cell Adhesion Molecule-1ConceptsLesser curvatureNF-κB subunitsInflammatory activationEndothelial cellsAtherosclerosis-prone sitesPro-inflammatory functionsInflammatory marker expressionNormal chow dietArch of aortaInitiation of atherosclerosisInflammatory markersOverall inflammationChow dietInflammatory pathwaysYoung miceAtherosclerosis-susceptible regionsConclusionThese dataICAM-1VCAM-1NF-κBRelA NF-κB subunitMarker expressionLow levelsFibronectin depositionInflammation
2011
Src and Caveolin-1 Reciprocally Regulate Metastasis via a Common Downstream Signaling Pathway in Bladder Cancer
Thomas S, Overdevest JB, Nitz MD, Williams PD, Owens CR, Sanchez-Carbayo M, Frierson HF, Schwartz MA, Theodorescu D. Src and Caveolin-1 Reciprocally Regulate Metastasis via a Common Downstream Signaling Pathway in Bladder Cancer. Cancer Research 2011, 71: 832-841. PMID: 21148751, PMCID: PMC4306590, DOI: 10.1158/0008-5472.can-10-0730.Peer-Reviewed Original ResearchConceptsActin stress fibersCav-1Active SrcStress fibersPhosphorylation of p190RhoGAPSrc protein levelsDownstream Signaling PathwaysCaveolin-1 expressionActivity of RhoACav-1 overexpressionTail vein inoculationRegulates MetastasisBladder cancerCommon downstreamHuman bladder cancer cellsPhosphorylated formSignaling pathwaysSrc levelsCell migrationBiochemical studiesLung metastasesMetastasis developmentSrc expressionBladder cancer cellsSrc
2010
Atheroprone Hemodynamics Regulate Fibronectin Deposition to Create Positive Feedback That Sustains Endothelial Inflammation
Feaver RE, Gelfand BD, Wang C, Schwartz MA, Blackman BR. Atheroprone Hemodynamics Regulate Fibronectin Deposition to Create Positive Feedback That Sustains Endothelial Inflammation. Circulation Research 2010, 106: 1703-1711. PMID: 20378855, PMCID: PMC2891748, DOI: 10.1161/circresaha.109.216283.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAortic DiseasesApolipoproteins EAtherosclerosisCells, CulturedDisease Models, AnimalEndothelium, VascularFeedback, PhysiologicalFibronectinsHemodynamicsHumansInflammationMechanotransduction, CellularMiceMice, Inbred C57BLMice, KnockoutNF-kappa BPlatelet Endothelial Cell Adhesion Molecule-1Pulsatile FlowRegional Blood FlowRNA InterferenceStress, MechanicalTime FactorsTransfectionUp-RegulationConceptsFN depositionAtheroprone flowPECAM-1FN expressionTranscription factor NF-kappaB.Platelet endothelial cell adhesion moleculeNF-kappaB activationNF-kappaB activityAtheroprone hemodynamicsHuman endothelial cellsEndothelial inflammationProinflammatory phenotypeAortic archInduction of fibronectinCarotid arteryCell adhesion moleculeExogenous fibronectinInflammatory signalingFN accumulationNF-kappaBSustained increaseNF-kappaB.Nuclear factorTransient increaseEndothelial cells
2009
The Subendothelial Extracellular Matrix Modulates JNK Activation by Flow
Hahn C, Orr AW, Sanders JM, Jhaveri KA, Schwartz MA. The Subendothelial Extracellular Matrix Modulates JNK Activation by Flow. Circulation Research 2009, 104: 995-1003. PMID: 19286608, PMCID: PMC2702158, DOI: 10.1161/circresaha.108.186486.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApolipoproteins EAtherosclerosisBasement MembraneCattleCell Culture TechniquesCells, CulturedCollagenDisease Models, AnimalEndothelial CellsEnzyme ActivationExtracellular MatrixFibronectinsHemorheologyInflammationIntegrinsJNK Mitogen-Activated Protein KinasesMiceMice, Inbred C57BLMice, KnockoutMitogen-Activated Protein Kinase KinasesOscillometryP21-Activated KinasesPhosphorylationRegional Blood FlowStress, Mechanical
2008
Endothelial Cell PECAM-1 Promotes Atherosclerotic Lesions in Areas of Disturbed Flow in ApoE-Deficient Mice
Harry BL, Sanders JM, Feaver RE, Lansey M, Deem TL, Zarbock A, Bruce AC, Pryor AW, Gelfand BD, Blackman BR, Schwartz MA, Ley K. Endothelial Cell PECAM-1 Promotes Atherosclerotic Lesions in Areas of Disturbed Flow in ApoE-Deficient Mice. Arteriosclerosis Thrombosis And Vascular Biology 2008, 28: 2003-2008. PMID: 18688018, PMCID: PMC2651147, DOI: 10.1161/atvbaha.108.164707.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAorta, AbdominalAorta, ThoracicApolipoproteins EAtherosclerosisBone Marrow CellsBone Marrow TransplantationCells, CulturedDietary FatsDisease Models, AnimalDisease ProgressionEndothelial CellsHumansMacrophagesMiceMice, Inbred C57BLMice, KnockoutNF-kappa BPlatelet Endothelial Cell Adhesion Molecule-1Regional Blood FlowRNA InterferenceRNA, Small InterferingStress, MechanicalVascular Cell Adhesion Molecule-1ConceptsEndothelial PECAM-1PECAM-1Aortic archAbdominal aortaNF-kappaBVascular cell adhesion molecule-1 expressionCell adhesion molecule-1 expressionAdhesion molecule-1 expressionCell adhesion molecule-1ApoE-deficient miceAtherosclerotic lesion sizeBone marrow transplantationAtherosclerotic lesion formationMolecule-1 expressionVCAM-1 expressionAdhesion molecule-1Endothelial cell adhesion molecule-1NF-kappaB activityNuclear NF-kappaBDisturbed flowMarrow transplantationMacrophage infiltrationLesser curvatureWestern dietDeficient mice