Granulocytes and Vascularization Regulate Uterine Bleeding and Tissue Remodeling in a Mouse Menstruation Model 英文参考文献.docVIP

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Granulocytes and Vascularization Regulate Uterine Bleeding and Tissue Remodeling in a Mouse Menstruation Model 英文参考文献.doc

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Granulocytes and Vascularization Regulate Uterine Bleeding and Tissue Remodeling in a Mouse Menstruation Model 英文参考文献

GranulocytesandVascularizationRegulateUterine BleedingandTissueRemodelinginaMouse MenstruationModel AstridMenning*,AlexanderWalter,MarionRudolph,IsabellaGashaw,Karl-HeinrichFritzemeier, LarsRoese TherapeuticResearchGroupOncology/GynecologicalTherapy,BayerHealthCarePharmaceuticals,Berlin,Germany Abstract Menstruation-associated disorders negatively interfere with the quality of life of many women. However, mechanisms underlyingpathogenesisofmenstrualdisordersremainpoorlyinvestigateduptodate.Amongothers,thisisbasedonalack of appropriate pre-clinical animalmodels. We here employ amousemenstruation model induced by primingmice with gonadalhormonesandapplicationofaphysicalstimulusintotheuterusfollowedbyprogesteroneremoval.Asinwomen, these events are accompanied by menstrual-like bleeding and tissue remodeling processes, i.e. disintegration of decidualizedendometrium,aswellassubsequentrepair.Wedemonstratethattheonsetofbleedingcoincideswithstrong upregulationofinflammatorymediatorsandmassivegranulocyteinfluxintotheuterus.Uterinegranulocytesplayacentral role in regulating local tissue remodeling since depletion of these cells results in dysregulated expression of matrix modifyingenzymes.Asdescribedhereforthefirsttime,uterinebloodlosscanbequantifiedbyhelpoftampon-likecotton pads. Using this novel technique, we reveal that blood loss is strongly reduced upon inhibition of endometrial vascularization and thus, is a key regulator of menstrual bleeding. Taken together, we here identify angiogenesis and infiltratinggranulocytesascriticaldeterminantsofuterinebleedingandtissueremodelinginamousemenstruationmodel. Importantly,our study providesatechnicalandscientific basis allowingquantification ofuterine bloodloss inmice and thus,assessmentoftherapeuticintervention,provinggreatpotentialforfutureuseinbasicresearchanddrugdiscovery. Citation: Menning A, Walter A, Rudolph M, Gashaw I, Fritzemeier K-H, et al. (2012) Granulocytes and Vascularization Regulate Uterine Bleeding and Tiss