Direct Sensing of Endothelial Oxidants by Vascular Endothelial Growth Factor Receptor-2 and c-Src 英文参考文献.docVIP

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Direct Sensing of Endothelial Oxidants by Vascular Endothelial Growth Factor Receptor-2 and c-Src 英文参考文献.doc

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Direct Sensing of Endothelial Oxidants by Vascular Endothelial Growth Factor Receptor-2 and c-Src 英文参考文献

DirectSensingofEndothelialOxidantsbyVascular EndothelialGrowthFactorReceptor-2andc-Src MonicaLee1,2,WingC.Choy1,3,Md.RuhulAbid1* 1DivisionofCardiothoracicSurgery,CardiovascularResearchCenter,BrownUniversityWarrenAlpertMedicalSchool,RhodeIslandHospital,Providence,RhodeIsland, UnitedStatesofAmerica,2TexasTechUniversityHealthSciencesCenter,SchoolofMedicine,Lubbock,Texas,UnitedStatesofAmerica,3DepartmentofMedicine,Beth IsraelDeaconessMedicalCenter,Boston,Massachusetts,UnitedStatesofAmerica Abstract Background: ADPH oxidase-derived reactive oxygen species (ROS) play important roles in redox homeostasis and signal transduction in endothelial cells (ECs). We previously demonstrated that c-Src plays a key role in VEGF-induced, ROS- dependentselectiveactivationofPI3K-AktbutnotPLCc-1-ERK1/2signalingpathways.Theaimofthepresentstudywasto understand howVEGFR-2-c-Srcsignalingaxis‘senses’NADPHoxidase-derivedROSlevelsandcouples VEGFactivation of c-SrctotheredoxstateofECs. Methodology/PrincipalFindings:Usingbiotinylatedprobethatdetectsoxidationofcysteinethiol(cys-OH)inintracellular proteins,wedemonstratethatVEGFinducedoxidativemodificationinc-SrcandVEGFR-2,andthatreductioninROSlevels using siRNA against p47phox subunit of Rac1-dependent NADPH oxidase inhibited this phenomenon. Co-immunoprecip- itationstudiesusinghumancoronaryarteryECs(HCAEC)showedthatVEGF-inducedROS-dependentinteractionbetween VEGFR-2 and c-Src correlated with their thiol oxidation status. Immunofluorescence studies using antibodies against internalizedVEGFR-2andc-SrcdemonstratedthatVEGF-inducedsubcellularco-localizationofthesetyrosinekinaseswere alsodependentonNADPHoxidsase-derivedROS. Conclusion/Significance: These results demonstrate that VEGF induces cysteine oxidation in VEGFR-2 and c-Src in an NADPH oxidase-derived ROS-dependent manner, suggesting that VEGFR-2 and c-Src can ‘sense’ redox levels in ECs. The dataalsosuggestthatthioloxidationstatusofVEGFR-2andc-Srccorrelateswiththeirabilitytophysicallyintera