Diminished Thrombogenic Responses by Deletion of the Podocalyxin Gene in Mouse Megakaryocytes 英文参考文献.docVIP

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Diminished Thrombogenic Responses by Deletion of the Podocalyxin Gene in Mouse Megakaryocytes 英文参考文献.doc

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Diminished Thrombogenic Responses by Deletion of the Podocalyxin Gene in Mouse Megakaryocytes 英文参考文献

DiminishedThrombogenicResponsesbyDeletionofthe PodocalyxinGeneinMouseMegakaryocytes MiguelPericacho2.,SoniaAlonso-Mart?′n1.,SusanaLarrucea3,ConsueloGonza′lez-Mancho′n1,2,Dar?′o Ferna′ndez2,Ine′sSa′nchez1,MatildeS.Ayuso1,2,RobertoParrilla1,2 * 1DepartmentofCellularandMolecularMedicine,CentrodeInvestigacionesBiolo′gicas(CSIC),Madrid,Spain,2CIBERdeEnfermedadesRaras(CIBERER),Madrid,Spain, 3LaboratoriodeInmunolog?′a,HospitaldeCruces,Baracaldo,Spain Abstract Podocalyxin(Podxl)isatypeImembranesialoproteinoftheCD34family,originallydescribedintheepithelialglomerular cells of thekidney (podocytes)in which itplaysanimportant function. Podxlcanalso be foundin megakaryocytes and platelets among other extrarenal places. The surface exposure of Podxl upon platelet activation suggested it could play somephysiologicalrole.ToelucidatethefunctionofPodxlinplatelets,wegeneratedmicewithrestrictedablationofthe podxlgeneinmegakaryocytesusingtheCre-LoxPgenetargetingmethodology.MicewithPodxl-nullmegakaryocytesdid notshowanyapparentphenotypicalchangeandtheirratesofgrowth,lifespanandfertilitydidnotdifferfromthefloxed controls. However, Podxl-null mice showed prolonged bleeding time and decreased platelet aggregation in response to physiologicalagonists.Thenumber,size-distributionandpolyploidyofPodxl-nullmegakaryocytesweresimilartothefloxed controls.Podxl-nullplateletsshowednormalcontentofsurfacereceptorsandnormalactivationbyagonists.However,the mice bearing Podxl-null platelets showed a significant retardation in the ferric chloride-induced occlusion of the carotid artery.Moreover,acutethrombosisinducedbythei.v.injectionofsublethaldosesofcollagenandphenylephrineproduced a smaller fall in the number of circulating platelets in Podxl-null mice than in control mice. In addition, perfusion of uncoagulatedbloodfromPodxl-nullmiceinparallelflowchambershowedreducedadhesionofplateletsandformationof aggregatesunderhighshearstress.ItisconcludedthatplateletPodxlisinvolvedinthecontrolofhemostasisactinga