ANG-1 TIE-2 and BMPR Signalling Defects Are Not Seen in the Nitrofen Model of Pulmonary Hypertension and Congenital Diaphragmatic Hernia 英文参考文献.docVIP

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ANG-1 TIE-2 and BMPR Signalling Defects Are Not Seen in the Nitrofen Model of Pulmonary Hypertension and Congenital Diaphragmatic Hernia 英文参考文献.doc

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ANG-1 TIE-2 and BMPR Signalling Defects Are Not Seen in the Nitrofen Model of Pulmonary Hypertension and Congenital Diaphragmatic Hernia 英文参考文献

ANG-1TIE-2andBMPRSignallingDefectsAreNotSeen intheNitrofenModelofPulmonaryHypertensionand CongenitalDiaphragmaticHernia HarrietJaneCorbett1,2*,MarilynGwenConnell1,DavidGarthFernig3,PaulDamionLosty1,2. ,Edwin ChitranJesudason1,2. 1Division of Child Health, Institute of Translational Medicine, The University of Liverpool, Liverpool, United Kingdom, 2Department of Paediatric Surgery, Alder Hey Children’sNationalHealthService(NHS)FoundationTrust,Liverpool,UnitedKingdom,3DepartmentofChemicalandStructuralBiology,InstituteofIntegrativeBiology, TheUniversityofLiverpool,Liverpool,UnitedKingdom Abstract Background:Pulmonaryhypertension(PH)isalethaldiseasethatisassociatedwithcharacteristichistologicalabnormalities of the lung vasculature and defects of angiopoetin-1 (ANG-1), TIE-2 and bone morphogenetic protein receptor (BMPR)- related signalling. We hypothesized that if these signalling defects cause PH generically, they will be readily identifiable perinatally in congenital diaphragmatic hernia (CDH), where the typical pulmonary vascular changes are present before birthandareaccompaniedbyPHafterbirth. Methods: CDH (predominantly left-sided, LCDH) was created in Sprague-Dawley rat pups by e9.5 maternal nitrofen administration.LeftlungsfromnormalandLCDHpupswerecomparedatfetalandpostnataltimepointsforANG-1,TIE-2, phosphorylated-TIE-2, phosphorylated-SMAD1/5/8 and phosphorylated-ERK1/2 by immunoprecipitation and Western blottingoflungproteinextractsandbyimmunohistochemistryonlungsections. Results:Innormallung,pulmonaryANG-1proteinlevelsfallbetweenfetalandpostnatallife,whileTIE-2levelsincrease. Over the corresponding time period, LCDH lung retained normal expression of ANG-1, TIE-2, phosphorylated-TIE-2 and, downstreamofBMPR,phosphorylated-SMAD1/5/8andphosphorylated-p44/42. Conclusion:InPHandCDHdefectsofANG-1/TIE-2/BMPR-relatedsignallingarenotessentialforthelethalvasculopathy. Citation:CorbettHJ,ConnellMG,FernigDG,LostyPD,JesudasonEC(2012)ANG-1TIE-2andBMPRSignallingDefectsAreNo