BAMBI Regulates Angiogenesis and Endothelial Homeostasis through Modulation of Alternative TGFβ Signaling 英文参考文献.docVIP

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BAMBI Regulates Angiogenesis and Endothelial Homeostasis through Modulation of Alternative TGFβ Signaling 英文参考文献.doc

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BAMBI Regulates Angiogenesis and Endothelial Homeostasis through Modulation of Alternative TGFβ Signaling 英文参考文献

BAMBIRegulatesAngiogenesisandEndothelial HomeostasisthroughModulationofAlternativeTGFb Signaling NicolasGuillot1,DmitrijKollins1,VictoriaGilbert1,SandhyaXavier2,JunChen2,MadeleineGentle1, AnandReddy1,ErwinBottinger1,RulangJiang3,MariaPiaRastaldi4,AlessandroCorbelli4, DetlefSchlondorff1* 1DepartmentofMedicine,MountSinaiSchoolofMedicine,NewYork,NewYork,UnitedStatesofAmerica,2DepartmentofMedicine,NewYorkMedicalCollege,Valhalla, NewYork,UnitedStatesofAmerica,3CincinnatiChildren’sHospitalMedicalCenter,Cincinnati,Ohio,UnitedStatesofAmerica,4RenalResearchLaboratory,Ospedale MaggiorPoliclinicoFondazioneD’AmicoperlaRicercasulleMalattieRenali,Milan,Italy Abstract Background:BAMBIisatypeITGFbreceptorantagonist,whoseinvivofunctionremainsunclear,asBAMBI2/2micelackan obviousphenotype. Methodology/PrincipalFindings:IdentifyingBAMBI’sfunctionsrequiresidentificationofcell-specificexpressionofBAMBI. ByimmunohistologywefoundBAMBIexpressionrestrictedtoendothelialcellsandbyelectronmicroscopyBAMBI2/2 mice showed prominent and swollen endothelial cells in myocardial and glomerular capillaries. In endothelial cells over- expressionofBAMBIreduced,whereasknock-downenhancedcapillarygrowthandmigrationinresponsetoTGFb.Invivo angiogenesiswasenhancedinmatrigelimplantsandinglomerularhypertrophyafterunilateralnephrectomyinBAMBI2/2 comparedtoBAMBI+/+miceconsistentwithanendothelialphenotypeforBAMBI2/2mice.BAMBI’smechanismofactionin endothelialcellswasexaminedbycanonicalandalternativeTGFbsignalinginHUVECwithover-expressionorknock-down of BAMBI. BAMBI knockdown enhanced basal and TGFb stimulated SMAD1/5 and ERK1/2 phosphorylation, while over- expressionpreventedboth. Conclusions/Significance:ThusweprovideafirstdescriptionofavascularphenotypeforBAMBI2/2mice,andprovidein vitroandinvivoevidencethatBAMBIcontributestoendothelialandvascularhomeostasis.Further,wedemonstratethatin endothelial cells BAMBI interferes with alternative TGFb signaling, most likely through the ALK 1 receptor, which may explainthep