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Mural Cell Associated VEGF Is Required for Organotypic Vessel Formation 英文参考文献
MuralCellAssociatedVEGFIsRequiredforOrganotypic
VesselFormation
LasseEvensen1,DavidR.Micklem1¤a,AnnaBlois1,SisselVikBerge1,NielsAars?ther1 ,Amanda
Littlewood-Evans2,JeanetteWood2¤b,JamesB.Lorens1*
1DepartmentofBiomedicine,UniversityofBergen,Bergen,Norway,2OncologyResearch,NovartisInstitutesforBioMedicalResearch,Basel,Switzerland
Abstract
Background:Bloodvesselscompriseendothelialcells,muralcells(pericytes/vascularsmoothmusclecells)andbasement
membrane.Duringangiogenesis,muralcellsarerecruitedtosproutingendothelialcellsanddefineastabilizingcontext,
comprisingcell-cellcontacts,secretedgrowthfactorsandextracellularmatrixcomponents,thatdrivesvesselmaturation
andresistancetoanti-angiogenictherapeutics.
Methods and Findings: To better understand the basis for mural cell regulation of angiogenesis, we conducted high
contentimaginganalysisonamicrotiterplateformatinvitroorganotypicbloodvesselsystemcomprisingprimaryhuman
endothelialcellsco-culturedwithprimaryhumanmuralcells.Weshowthatendothelialcellsco-culturedwithmuralcells
undergoanextensiveseriesofphenotypicchangesreflectiveofseveralfacetsofbloodvesselformationandmaturation:
Loss of cell proliferation, pathfinding-like cell migration, branching morphogenesis, basement membrane extracellular
matrix protein deposition, lumen formation, anastamosis and development of a stabilized capillary-like network. This
phenotypic sequence required endothelial-mural cell-cell contact, mural cell-derived VEGF and endothelial VEGFR2
signaling. Inhibiting formation of adherens junctions or basement membrane structures abrogated network formation.
Notably,inhibitionofmuralcellVEGFexpressioncouldnotberescuedbyexogenousVEGF.
Conclusions:Theseresultssuggestauniqueroleformuralcell-associatedVEGFindrivingvesselformationandmaturation.
Citation:EvensenL,MicklemDR,BloisA,VikBergeS,Aars?therN,etal.(2009)MuralCellAssociatedVEGFIsRequiredforOrganotypicVesselFormation.PLoS
ONE4(6):e5798.doi:10.1371/journal.pone.0005798
Editor:YihaiCao,KarolinskaInstit
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