Vascularendothelialgrowthfactor(VEGF)playsakeyroleinphysiologicalbloodvesselformationandpathologicalangiogenesissuchastumorgrowthandischemicdiseases.HypoxiaisapotentinducerofVEGFinvitro.TheincreaseinsecretedBIOLOGicallyactiveVEGFproteinfromcellsexposedtohypoxiaispartlybecauseofanincreasedtranscriptionrate,mediatedbybindingofhypoxia-inducIBLefactor-1(HIF1)toahypoxiaresponsiveelementinthe5"-flankingregionoftheVEGFgene.bHLH-PAStranscriptionfactorthatinteractswiththeAhreceptornucleartranslocator(Arnt),anditspredictedaminoacidsequenceexhibitssignificantsimilaritytothehypoxia-induciblefactor1alpha(HIF1a)product.HLFmRNAexpressioniscloselycorrelatedwiththatofVEGFmRNA..ThehighexpressionlevelofHLFmRNAintheO2deliverysystemofdevelopingembryosandadultorganssuggeststhatinanormoxicstate,HLFregulatesgeneexpressionofVEGF,variousglycolyticenzymes,andothersdrivenbytheHREsequence,andmaybeinvolvedindevelopmentofbloodvesselsandthetubularsystemoflung.VEGFexpressionisdramaticallyinducedbyhypoxiadueinlargeparttoanincreaseinthestABIlityofitsmRNA.HuRbindswithhighaffinityandspecificitytotheVRSelementthatregulatesVEGFmRNAstabilitybyhypoxia.Inaddition,aninternalribosomeentrysite(IRES)ensuresefficienttranslationofVEGFmRNAevenunderhypoxia.TheVHLtumorsuppressor(vonHippel-Lindau)regulatesalsoVEGFexpressionatapost-transcriptionallevel.ThesecretedVEGFisamajorangiogenicfactorthatregulatesmultipleendothelialcellfunctions,includingmitogenesis.CellularandcirculatinglevelsofVEGFareelevatedinhematologicmalignanciesandareadverselyassociatedwithprognosis.Angiogenesisisaverycomplex,tightlyregulated,multistepprocess,thetargetingofwhichmaywellproveusefulinthecreationofnoveltherapeuticagents.Currentapproachesbeinginvestigatedincludetheinhibitionofangiogenesisstimulants(e.g.,VEGF),ortheirreceptors,blockadeofendothelialcellactivation,inhibitionofmatrixmetalloproteinases,andinhibitionoftumorvasculature.Preclinical,phaseI,andphaseIIstudiesofbothmonoclonalantibodiestoVEGFandblockersoftheVEGFreceptortyrosinekinasepathwayindicatethattheseagentsaresafeandofferpotentialclinicalutilityinpatientswithhematologicmalignancies.

Contributor:KosiGramatikoff,PhD

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