Polo-like kinase 2 regulates angiogenic sprouting and blood vessel development

摘要

Angiogenesisreliesonspecializedendothelialtipcellstoextendtowardguidancecuesinordertodirectgrowingbloodvessels.Althoughmanyofthesignalingpathwaysthatcontrolthisdirectionalendothelialsproutingarewellknown,thespecificcellularmechanismsthatmediatethisprocessremaintobefullyelucidated.Here,weshowthatPolo-likekinase2(PLK2)regulatesRap1activitytoguideendothelialtipcelllamellipodiaformationandsubsequentangiogenicsprouting.Usingacombinationofhigh-resolutioneminvivo/emimagingofzebrafishvasculardevelopmentandahumanumbilicalveinendothelialcell(HUVEC)eminvitro/emcellculturesystem,weobservedthatlossofemPLK2/emfunctionresultedinareductioninendothelialcellsproutingandmigration,whereasoverexpressionofemPLK2/empromotedangiogenesis.Furthermore,wediscoveredthatPLK2maycontrolangiogenicsproutingbybindingtoPDZ-GEFtoregulateRAP1activityduringendothelialcelllamellipodiaformationandextracellularmatrixattachment.Consistentwiththesefindings,constitutivelyactiveRAP1couldrescuetheendothelialcellsproutingdefectsobservedinzebrafishandHUVECemPLK2/emknockdowns.Overall,thesefindingsrevealaconservedPLK2-RAP1pathwaythatiscrucialtoregulateendothelialtipcellbehaviorinordertoensurepropervasculardevelopmentandpatterninginvertebrates./p/div