Endogenous VEGF Is Required for Visual Function Evidence for a Survival Role on Müller Cells and Photoreceptors 英文参考文献.docVIP

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Endogenous VEGF Is Required for Visual Function Evidence for a Survival Role on Müller Cells and Photoreceptors 英文参考文献.doc

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Endogenous VEGF Is Required for Visual Function Evidence for a Survival Role on Müller Cells and Photoreceptors 英文参考文献

EndogenousVEGFIsRequiredforVisualFunction: EvidenceforaSurvivalRoleonMu¨llerCellsand Photoreceptors MagaliSaint-Geniez1,2,ArindelS.R.Maharaj1,TonyE.Walshe1,2,BuddA.Tucker1,2,EiichiSekiyama1,2 , TomokiKurihara1,DianeC.Darland4,MichaelJ.Young1,2,PatriciaA.D’Amore1,2,3 * 1SchepensEyeResearchInstitute,HarvardMedicalSchool,Boston,Massachusetts,UnitedStatesofAmerica,2DepartmentofOphthalmology,HarvardMedicalSchool, Boston,Massachusetts,UnitedStatesofAmerica,3DepartmentofPathology,HarvardMedicalSchool,Boston,Massachusetts,UnitedStatesofAmerica,4Universityof NorthDakota,GrandForks,NorthDakota,UnitedStatesofAmerica Abstract Background: Vascular endothelial growth factor (VEGF) is well known for its role in normal and pathologic neovascularization. However, a growing body of evidence indicates that VEGF also acts on non-vascular cells, both developmentallyaswellasintheadult.Inlightofthewidespreaduseofsystemicandintraocularanti-VEGFtherapiesfor thetreatmentofangiogenesisassociatedwithtumorgrowthandwetmaculardegeneration,systematicinvestigationofthe roleofVEGFintheadultretinaiscritical. MethodsandFindings:UsingimmunohistochemistryandLac-Zreportermouselines,wereportthatVEGFisproducedby variouscellsintheadultmouseretinaandthatVEGFR2,theprimarysignalingreceptor,isalsowidelyexpressed,withstrong expressionby Mu¨ller cells and photoreceptors. Systemic neutralization of VEGF wasaccomplished in mice by adenoviral expressionofsFlt1.After14daysofVEGFneutralization,therewasnoeffectontheinnerandouterretinavasculature,buta significantincreaseinapoptosisofcellsintheinnerandouternuclearlayers.Byfourweeks,theincreaseinneuralcelldeath wasassociatedwithreducedthicknessoftheinnerandouternuclearlayersandadeclineinretinalfunctionasmeasuredby electroretinograms.siRNA-basedsuppressionofVEGFexpressioninaMu¨llercelllineinvitrosupportstheexistenceofan autocrineroleforVEGFinMu¨llercellsurvival.Similarly,theadditionofexogenousVEGFtofreshlyisolatedphotoreceptor cellsandouter-nuclear-layerexplantsdemons