Beneficial Effects of Estrogen in a Mouse Model of Cerebrovascular Insufficiency 英文参考文献.docVIP

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Beneficial Effects of Estrogen in a Mouse Model of Cerebrovascular Insufficiency 英文参考文献.doc

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Beneficial Effects of Estrogen in a Mouse Model of Cerebrovascular Insufficiency 英文参考文献

BeneficialEffectsofEstrogeninaMouseModelof CerebrovascularInsufficiency NaohitoKitamura1.,RunaAraya1.,MoekoKudoh1,HaruoKishida1,TetsuyaKimura2 ,Miyuki Murayama2,AkihikoTakashima2,YurikoSakamaki3,TsutomuHashikawa3,ShingoIto4,SumioOhtsuki4, TetsuyaTerasaki4,Ju¨rgenWess5,MasahisaYamada1* 1YamadaResearchUnit,RIKENBrainScienceInstitute,Saitama,Japan,2LaboratoryforAlzheimer’sDiseases,RIKENBrainScienceInstitute,Saitama,Japan,3Research ResourceCenter,RIKENBrainScienceInstitute,Saitama,Japan,4DepartmentofMolecularBiopharmacyandGenetics,TohokuUniversity,Sendai,Japan,5Laboratoryof BioorganicChemistry,NationalInstituteofDiabetesandDigestiveandKidneyDiseases,Bethesda,Maryland,UnitedStatesofAmerica Abstract Background:TheM5muscarinicacetylcholinereceptorisknowntoplayacrucialroleinmediatingacetylcholinedependent dilationofcerebralbloodvessels.Previously,wereportedthatmaleM5muscarinicacetylcholineknockoutmice(M5R2/2 mice)sufferfromaconstitutiveconstrictionofcerebralarteries,reducedcerebralbloodflow,dendriticatrophy,andshort- termmemoryloss,withoutnecrosisand/orinflammationinthebrain. Methodology/Principal Findings: We employed the Magnetic Resonance Angiography to study the area of the basilar arteryinmaleandfemaleM5R2/2mice.HereweshowthatfemaleM5R2/2micedidnotshowthereductioninvasculararea observed in male M5R2/2 mice. However, ovariectomized female M5R2/2 mice displayed phenotypic changes similar to maleM5R2/2mice,stronglysuggestingthatestrogenplaysakeyroleintheobservedgenderdifferences.Wefoundthat 17b-estradiol(E2)inducednitricoxidereleaseandERKactivationinaconditionalimmortalizedmousebraincerebrovascular endothelialcellline.AgonistsofERa,ERb,andGPR30promotedERKactivationinthiscellline.Moreover,invivomagnetic resonanceimagingstudiesshowedthatthecrosssectionofthebasilararterywasrestoredtonormalinmaleM5R2/2mice treatedwithE2.TreatmentwithE2alsoimprovedtheperformanceofmaleM5R2/2miceinacognitivetestandreducedthe atrophyofneuraldendritesinthecerebralcortexandhippocampus.M5R2/2micea