journal-club-2015-12-2

JOURNALCLUB2015.12.02Background•Atherosclerosisisaprogressivedisorderinitiatedbybiomechanicalforcesinareasofthevasculartreesubjectedtodisturbedbloodflowandanumberofsystemicfactors,includinghyperlipidemia,smoking,anddiabetes.•Thebuildup,growth,andruptureoftheplaquehaveallbeenassociatedwiththepresenceofsystemicandvascularwallinflammation.•Butthemechanism(s)ofinflammation-inducedatheroscleroticdiseaseprogressionremainsobscure,whileeffortstohaltdiseaseprogressionbyantiinflammatorytherapieshavefailedinclinicaltrial.Whatisendothelial-to-mesenchymaltransition(EndMT)?•EndMTischaracterizedbyachangeinphenotypeofnormalendothelialcells(ECs)thatassumetheshapeandpropertiesofmesenchymalcells(fibroblasts,smoothmusclecells[SMCs]),includingenhancedproliferationandmigration;secretionofextracellularmatrixproteins,suchasfibronectinandcollagen;andexpressionofvariousleukocyteadhesionmolecules.•Recentstudieshavedocumentedahighincidenceofendothelial-to-mesenchymaltransition(EndMT)inanumberofpathologicalconditionsassociatedwithinflammation.PreviousstudyHypothesis:BiomechanicalandinflammatorystimulireduceprotectiveendothelialFGFR1signalingtodriveEndMTandprogressionofatheroscleroticplaque.Researchrouteinflammatorycytokinesandoscillatoryshearstress①reducedendothelialFGFR1expression②activationofendothelialTGF-βsignaling③extensivedevelopmentofEndMTprogressionofatherosclerosiscellculture(HUVECs)Cdh5-CreERT2mT/mGApoe–/–Frs2afl/flmiceleftmaincoronaryarteriesfrom43patientsinduceinduceCytokinetreatmentdownregulatesFGFR1expressionandincreasesendothelialcellinflammationandEndMTShearstressdownregulatesFGFR1expressionandupregulatesTGF-βsignalinginvitrooscillatingshearstress(OSS)laminarshearstress(LSS)ShearstressdownregulatesFGFR1expressionandupregulatesTGF-βsignalinginvitroShearstressdownregulatesFGFR1expressionandupregulatesTGF-βsignalinginvivo.Apoe–/–miceEndMTinmouseatherosclerosis.cellmousehumanFGFsignalingactivityandEndMTextentinamouseatherosclerosismodel.Cdhr5-CreERT2mT/mGApoe–/–micepromoterfluorescentreporterFGFsignalingactivityandEndMTextentinamouseatherosclerosismodel.GeneratedCdh5-CreERT2mT/mGApoe–/–Frs2afl/flmice(FRS2αECKOApoe–/–miceFRS2α:thegeneencodingthepan-FGFRadaptormoleculeEffectofendothelialFGFsignalingsuppressiononatherosclerosisinmiceafter4weeksofHFDEarlyonsetofatherogenesisinFRS2αECKOApoe–/–miceEffectofendothelialFGFsignalingsuppressiononatherosclerosisinmiceafter4monthsofHFD.EffectofendothelialFGFsignalingsuppressiononinflammationandEndMTmarkergeneexpressioninmiceEffectofendothelialFGFsignalingsuppressiononinflammationandEndMTmarkergeneexpressioninmiceEffectofendothelialFGFsignalingsuppressiononinflammationandEndMTmarkergeneexpressioninmiceEndMTinhumanatherosclerosis.cellmousehumanMorphologicalassessmentandclassificationdiseaseseverityinhumanleftmaincoronaryarteries.[I/M]:intima-tomediaratioExpressionofFGFR1wasreducedto47.6%oftheluminalendotheliuminpatientswithmoderateCADand11.1%inpatientswithsevereCADp-SMAD2,amarkerofactivatedTGF-βsignaling,increasedwithdiseaseseverity①inverselinearrelationshipbetweentheI/MratioandnumberofECsexpressingFGFR1②positivecorrelationwiththenumberofECsexpressingp-SMAD2③FGFR1expressionwasinverselycorrelatedwithTGF-βsignalingEndMTmarkersexpressionintheendotheliumofhumancoronaryarteriesastrongcorrelationbetweenthenumberofECsexpressingNOTCH3andSM22αandtheI/MratioExpressionofTheextracellularmatrixproteinscollagenandfibronectinintheendotheliumofhumancoronaryarteriesastronglinearrelationshipbetweenincreasingendothelialexpressionofcollagenandfibronectinanddiseaseseverityWithincreasingCADseverity,luminalendothelialexpressionofICAM-1andVCAM-1areincreasing.astrongcorrelationbetweenincreaseinfibronectindepositionandICAM-1andVCAM-1expressionSummary•TheseobservationsestablishanassociationbetweentheseverityofCADandlossofendothelialFGFR1expressionaswellasbetweenactivationofendothelialTGF-βsignalingandtheextentofEndMT.Atherosclerosisprogression