JOEBXJ1VCMJTIJOHPSQPSBUJPO F4DJFOUJmD8PSMEPVSOBM 7PMVNFrSUJDMFrQBHFT eSci ID: 936804
Download Pdf The PPT/PDF document "ReviewArticleAtherosclerosisandAtheromaP..." is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.
ReviewArticleAtherosclerosisandAtheromaPlaqueRupture:NormalAnatomyofVasaVasorumandTheirRoleAssociatedwithAtherosclerosisZhonghuaSunDisciplineofMedicalImaging,DepartmentofImagingandAppliedPhysics,CurtinUniversity,GPOBoxU,Perth,WA,AustraliaCorrespondenceshouldbeaddressedtoZhonghuaSun;z.sun@curtin.edu.auReceivedAugust;AcceptedDecember;PublishedMarchAcademicEditors:M.V.SinghandE.SkalidisCopyright©ZhonghuaSun.isisanopenaccessarticledistributedundertheCreativeCommonsAttributionLicense,whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.Atherosclerosisisprimarilyadegenerativedisorderrelatedtoagingwithachronicinammatorycomponent.erearedi erencesinexpressionamongdi erentvascularbeds,inictingarangeofvasculardiseases.emajorityofstudiesfocusontheinnerandmedialvascularlayers,whicharea ectedatthedevelopmentofatherosclerosis.Recentevidenceshowsthattheouterlayerofbloodvessels,composedoftheadventitiallayerandthevasavasorum,notonlyplaysasigni cantroleinmaintainingvesselintegrity,butalsoreactstoatheroma.Whatisnotclearistheextentofcontributionoftheouterlayertotheprocessofatherosclerosis.Isitinvolvedintheinitiation,progression,andclinicalexpressionofatheroma?Istheinammationassociatedwithatheromalimitedtobeingmerelyreactiveoristhereaproactiveelement?ispaperprovidesanoverviewofthenormalanatomyofvasavasorumandpotentialmechanismofplaqueformationduetovascularinjury(vasavasorum)andmicrohemorrhage.1.Introductionerehasbeenaslowbutrelentlessinterestintheroleofthevasavasorum,theanatomyoftheirorigins,andtheirbranchdistributionduetotheirpossibleroleinatherogenesis[coronaryinterventions[],andinresponsetoriskfactorsforatherosclerosis[].Shouldatherogenesisbeshowntobeemanatingprimarilyfromthevasavasorumandnotviatheintimaliningthelumen,thenthiswillbeaparadigmshi inourthinkingofatherosclerosis.Itisaplausiblehypothesisthatwouldexplainmuch,includingmanyofthecomplicationsofdiabetesmediatedthroughmicrovessels.Cardiovasculardiseaseisthemajorcauseofmortalityandmorbidityindevelopedcountriesanditsprevalenceisincreasingindevelopingcountries,andatherosclerosisisresponsibleformanyoftheseveremanifestations,includ-ingmyocardialischemia,acutemyocardialinfarction,heartfailure,andstroke.Atherosclerosisisthemaincauseofamputationinpopulationsnotatwar.Itisimplicatedinaorticandothermajorvesseldiseasesandtheirpotentialforadverseevents.Duringplaquedevelopmentmanyproangiogenicpathwaysarereactivatedandthisleadstoformationofimmaturebloodvesselspronetorupture[].In ltrationofmicrovesselsintothemedia,intima,andplaquesoriginatesprimarilyfromproliferatingvasavasorum(themicrovesselssupplyingthemajorarteries).Knownstatisticallyprovenriskfactorsforthedevelopmentofatherosclerosisarewellpub-lishedandcanbeclassi edintoprecursorsandacceleratorss].Highbloodpressureisacentralriskfactorforthosegeneticallypredeterminedandanacceleratorinallcausesofhypertension.Vastamountsofmoneyarecommittedtoitscontrolandthecostbene tcouldbeimproved.Itiswell-knownthataninammatoryprocessoccurswithinthearterialwallatthesiteofadevelopingplaquee ],andthemechanismofinjurytotheintimaandlipidin ltrationofthemediaistheacceptedatherogenicpathway,whichisconsideredreactivetotheatheroma.ereisevidencethatowshearstressarisesfromdisturbedowfromprotrudingplaquewithvacuolationandturbulencethatcausefurtherintimaldisruption,andthishasbeensuggestedasamechanismforexcessbloodlipidstofueldepositionintoplaquesfromthelumenofthevessel. ) J O E B X J 1 V C M J T I J O H $ P S Q P S B U J P O F 4 D J F O U J m D 8 P S M E + P V S O B M 7 P M V N F \r " S U J D M F * % \r Q B H F T eScienti cWorldJournalehypothesisoft
heinitiatingprocessstartinginthewallofthearteryandtheinjuryhealingcycleinavulnerablesiteprovidingtheongoingstimulusthatperpetuatesthefor-mationoftheatheroscleroticplaquesdeservesinvestigation.eacceptedmechanismsforatherogenesisdonotexplainwhyatheromaisuniquelyanarteriallesionnotinvolvingveinsunlesstheyarearterialised;thatis,itisnotadiseaseoftheyoungandifwealllivelongenougheachoneofuswilldevelopanatheromatouslesion.Itisadiseaseinpre-dictablesitesthatareclearlystresssites.Pulsatilecontinuouspressure,notow,isthepeculiarparameterrelatedtoarterialdisease.Compliance,capacitance,andwater-hammere ectsareconspicuousonlybytheirabsenceintheargumentsforatherogenesisbutarelikelytobekeyassociatesofbloodpressureforces.Betterunderstandingofthemechanismsofatherogenesisisthekeytoimprovingprophylacticandmanagementoptionsbasedontheunderstandingofthephysicsandscienceofaphysicalparameter,thatis,centraltothediseaseanditsmanagement.Plaqueangiogenesishasbeenacceptedtoplayafun-damentalroleinthepathophysiologicaldevelopmentofatherosclerosis,providingnutrientstothedevelopingandexpandingintimaandalsopotentiallycreatinganunstablehemorrhagicenvironmentpronetorupture[].eexpressionofintimalneovesselsisdirectlyrelatedtothestageofplaquedevelopment,thepresenceofsymptomaticdisease,andtheriskofplaquerupture.Angiogenesisisinvolvedinthedevelopmentofatherosclerosisandassociatedwithclinicalsyndromesinthecoronarycirculationandinthecontextofsymptomaticcarotidocclusivedisease[].Inthepresenceofatherosclerosis,intimalneovascularizationarisesmostfrequentlyfromthedensenetworkofvesselsintheadventitia,adjacenttoaplaque,ratherthanfromthemainarterylumen.Astrongpositivecorrelationwasobservedbetweenthedegreeofadventitialangiogenesisandintimalthickening[].Duringendarterectomyofcarotidlesionssubintimalhemorrhagesandintraplaquehemorrhagesarefrequentlyseenintheabsenceofanyvisiblebreachintheintimaandtheinferenceisthatthesearederivedfromvasavasorumsystemsratherthanfrombloodinthevessellumen.Newbloodvesselsmayhaveanactiveroleinregu-latingplaquemetabolicactivityandactivelypromotingitsgrowthbeyondthecriticallimitsofdi usionfromthearterylumen.esenewbloodvessels,byprovidingthenecessaryconduitsforthetransferofnutrients,growthfactors,andmetabolicproducts,couldeventuallycontroltheprocessesthatgovernplaqueprogression[].esechangesinthevasavasorumarereactivelatechangeswithestablishedplaque.emicrovascularityrenderstheplaquevulnerabletointraplaquehemorrhageandpredictableadverseclinicalconsequence.Inotherwords,thehypothesisisthatthesechangesandeventsaretheendpointofaninjuryandhealingcycleandthatmicrointramuralhemorrhagefromrupturedpenetratingbranchesofthevasavasoruminhighintramuralstresspointscreatethenidusthatthenleadstothewholeprocessofatherosclerosis.ispaperprovidesanoverviewofthenormalanatomyofvasavasorumandpotentialmechanismofplaqueformationduetovascularinjury(vasavasorum)andmicrohemorrhage.2.VasaVasorum:NormalAnatomyandDistributionAcceptedmechanismfornourishmentofarteriesisachievedbydi usionfromthelumenofthevesselandfromvasavasorum[].Inhumans,vesselswithwallslessthansmoothmusclecelllayersthicknormallydonothavevasavasorum[],andvesselslessthan. mmlumendiameterdonothavevasavasorum[].Mostnormalarterieshaveanextensivenetworkofvasavasoruminadventitia.Inthethoracicaorta,branchesofadventitialvasavasorumpenetrateintothemediaandprovideanimportantsourceofnourishment.Insmallervessels,suchascoronaryarteries,vasavasorumareseeninadventitiabuthaverarelybeenimagedinmedia[].However,astudyofoveronehundredharvestedhumanheartswithsiliconinfusionofthecoronaryvesselsandvideoacquisitionofowanddistributionshowedvasavasorumfeedingpenetratingvesselsasfarastheinnerlayersofthemedia[Vasavasorumhavetree-likestructure,contrarytonet
-workinmostpartsofthebody;therefore,vasavasorumareconsideredfunctionalendarteriesratherthanafunctionalnetwork[].SchoenenbergerandMuellerdescribedthreetypesofvasavasoruminthearterialwallbasedonananimalexperiment[]:thevasavasorumexterna(VVE)andvasavasoruminterna(VVI)supplythearterialwallwithoxygenatedblood,andthevenousvasavasorum(VVV)drainthearterialwallintoconcomitantveins(Figure).eauthorsde nedtheVVEasarisingfrommajorbranchessuchasintercostalarteries,andtheVVIasoriginatingfromthemainlumenoftheaorta.Withtheuseofmicro-CTtechnology,Gossletal.forthe rsttimedemonstratedboththedi erenttypesandthe necharacteristicsofcoronaryvasavasorum(Figuree ].eirresultsindicatedthatthebranchingarchitectureofthevasavasorumtreesissimilartothatofvasculatureingeneral.Fromwheredothecoronaryarteriesderivetheirvasavasorumandbloodsupply?BargerandBeeuwkesIII[intheirstudyconcludedthatthepenetratingbranchesofthevasavasorumarethepathwayofthenourishmentofthebasementmembraneoftheintimabecausenovasavasorumorvascularchannelsweredemonstratedinthisstudy,emanatingfromthelumenofthevessel.ecoronaryvesselsareasubset,albeitvitallyspecial,ofthearterialtreeandapproximatelythesizeofmediumsizedvessels.Ifthevasavasorumariseonlyfromtheadventitiainthecoronaryvesselsandfromthelumenandadventitiaintheaorta,thisimpliesastrati cationofsizeofvesselandoriginofitsbloodsupply.isknowledgecouldbedecisiveindeterminingwhichvasculardiseaseresults.Forexample,dissectionsofthethoracicaortaifthemuralbloodsupplyislumenderivedorocclusionsofthemajorandmediumsizedvesselsifvasavasorumderived.Considerforamomentwhyiatrogenicbreachesintheintimaleadtodissectionsofvesselsotherwisepronetoatheroscleroticocclusionandrarelyifeverspontaneousdissection,whereastheaortaispronetodissectionfromintramuralexposuretodirectluminalpressurebyintimalbreachandpronetospontaneousdissectionsfromrupturedVVI. eScienti cWorldJournal Vasa vasoruminternaArtery lumenWall Vasa vasorumexterna Venousvasa vasorumVein F:Sketchesofthethreetypesofvasavasorumfoundinthewallofcowaortae(inspiredbySchoenenbergerandMueller[]).IntheSchoenenbergerandMuellerstudy,VVI(a)originateddirectlyfromtheaortasmainlumen,andVVE(b)originatedfromintercostalbranchesderivingfromthemainlumenanddivedbackintotheaorticwall.VVV(c)developedintheaorticwalland nallydrainedintobranchesofconcomitantveins(reprintwithpermissionfrom[Galilietal.reportedinapigmodeladi erenceinvasavasorumdensitythroughoutdi erentvascularbedsinhealthyvessels[].Usingmicro-CT,theydemonstratedstructuralheterogeneityoftheadventitialvasavasorumamongdi erentvascularbeds.Similarly,Hildebrandtetal.demonstratedasigni cantdi erenceinthevasavasorumdensitythroughoutthearterialsysteminhumans[eirresultsshowedthatvasavasorumdensityishigherincoronaryarteriescomparedtorenalandfemoralarteries,supportingtherelationbetweenvasavasorumandthesusceptibilitytodevelopatherosclerosisindi erentvascularbedsinhumans.ereasonveinsandthenormalpulmonaryarterydonotdevelopatherosclerosiscanbeexplainedbythefactthatthetransmuraluxofsoluteisdiminishedduetothelowvenousandpulmonaryarterypressures.Furthermore,thesevasavasorummaynevergetcompressedduringtheentirecardiaccycleduetotheselumenpressuresbeinglowerthanthepressurewithinthearterialvasavasorum,thusmaintainingadequateowinthevasavasorum[3.VasaVasorum:AssociationwithPlaqueFormationandRuptureeadventitia,media,andtheatheroscleroticplaquesofthecoronaryandcarotidarterieshavetheirownnutritionsupply:thevasavasorum,anetworkofsmallmicrovessels.Whenatherosclerosisdevelops,thevasavasorumincreaseincludingplaqueneovascularization,whichisthoughttoplayanimportantroleintheprogressionofatherosclerosis.eextensivevasavasorumnetworkcanfunctionasaconduitforentryofmacrophagesandinammatoryfactorsthatm
aypromotetheprogressionofangiogenesisandplaqueformation.Inhibitionofangiogenesishasbeenshowntoreducemacrophagesintheplaqueandaroundthevasavasorum[evasavasorumhavebeenthesubjectofconsiderableinterestformorethanacentury.econceptthattheadventitialvasavasorumofhumancoronaryarteriesplayaroleintheformationofatheroscleroticplaquesdatesbacktotheworkofKoester[]andWinternitzetal.[]andwasrevivedbyBargeretal.[],whoclearlyshowedinpostmortemsamplesthatcoronaryatheroscleroticsegmentspresentarichvascularnetworkextendingfromtheadventitiatothefullthicknessofmediaandintima.Ithassubsequentlybeenassumedthatthedensityofnewlyformedvasavasoruminresponsetoinjuryisproportionaltovesselstenosis[ ..VasaVasorum:AssociationbetweenVascularIn am-mationandAtherosclerosis.Vascularinammationandatherosclerosishavetraditionallybeenconsideredaninside-outresponse,whichemphasisesthecentralrolethatinammatoryresponsesareinitiatedattheluminalsurfacee].However,thereisgrowingevidencetosupportanewparadigmofanoutside-inhypothesis,inwhichvascularinammationisinitiatedintheadventitiaandprogressesinwardtowardthemediaandintima.efunctionalsigni canceoftheadventitiaincardiovasculardiseasehas eScienti cWorldJournal mm F:Volume-renderedmicro-CTimageofaVVV(yellow).(a)Inadditiontothele anteriordescendingcoronaryartery(right,pink)andtheconcomitantvein(le ,pink),the gureshowsthecomplexstructureoftheVVV,which nallydrainsintoabranch(whitearrow)oftheconcomitantvein((b),displayedatto(a)).eVVVdevelopsinsidethecoronaryarterywallandformsthiscomplextree-likestructure(reprintwithpermissionfrom[beenexploredformanyyears;however,onlyinrecentyears,supportingdataareavailableintheliteraturetodemonstrateinammationoccurringintheadventitiaassociatedwithcardiovascularpathogenesis[erelationshipbetweentheadventitialvasavasorumandthedevelopmentofatherosclerosisisfurthersupportedbyobservationsinbothexperimentalstudiesandhumansubjects.Lowincidenceofatherosclerosisisassociatedwithasigni cantlylowervasavasorumdensityinanimalstudiesudies,].Intraplaquehemorrhageiscommoninadvancedatheroscleroticlesions,anditsoccurrenceisconsideredanimportanteventinthemanifestationofatheroscleroticdisease,causingacuteprocessessuchasmyocardialinfarctionaswellascerebrovascularandperipheralacuteischemiaa,].Previousstudieshavedemonstratedtheassociationbetweenplaqueneovascularityandquantityofintraplaquehemorrhage[].Galilietal.intheirstudyconcludedthatthemicrovesselswhicharesmallerindiameterthanthe rstordervasavasorumarelessmatureandmightbemoresusceptibletohemorrhage,especiallyinthepresenceofhypertension[].Gossletal.intheiranimalexperi-mentsobservedsigni cantvasavasorumneovascularizationwithhighervascularvolumefractionintheproximalle anteriordescendinginpigswithhypercholesterolemiawhencomparedtothecontrolanimals[].Furthermore,alinkbetweenmicrovesselsandplaqueinstabilitywasidenti edinastudyconsistingof advancedhumanplaques[Morenoetal.noticedthatvesselwallandplaquemicrovesselsareincreasedinrupturedatheroscleroticplaques,suggestingacontributoryroleforneovascularizationofvasavasorumintheprocessofplaquerupture. . .VasaVasorum:AssociationbetweenVasaVasorumGrowthandPlaqueDevelopment.Research ndingsgener-allysupportthepossibilityofcorrelationbetweenthegrowthofvasavasorum,plaqueneovascularization,andplaquedevelopment[ equestionremainstobeanswered,however:whatstimulatesplaqueneovascularization?Evidenceshowsthatcyclicstrainincreasestubulogenesisbyendothe-lialcellsviavariouspathways[].ecyclicapplicationofstraintriggerstheendothelialandsmoothmusclecellsinthearterialwallstimulatingneovascularizationinthevasavasorum[].Agingofthearteriesorsti eningofthearterial eScienti cWorldJournalwallwithincreasingagecouldleadtoanincreasedapplica
-tionofcyclicstrain.Itiswell-knownthatthecomplianceofthearteriesdecreaseswithincreasingage;thatis,thearteriesgetsti erwithage[].Whenthearterialwallsti ens,shearstressontheendotheliumbythepulsationmightincreasedisplacementofthearterywithrespecttothesurroundingtissue[].isresultsinanincreaseinshearstrainintheadventitiallayerthatmightleadtothevasavasoruminjuryandsubsequentdevelopmentofvulnerableplaques.Manyexperimentalmeasurements(bothinvivoandvivo)havebeenconductedtodeterminetheparametersofthestrainenergycorrelations,whichwerefoundtochangesigni cantlythroughaging,disease,andchangeinmechanicalload[].Shearingandstress/strainleadingtofatiguefracturesandintramuralhematomaformationfromdisruptedvasavasorumarecon rmedtobeafactorinatheroscleroticdevelopmentandpotentiallyasigni cantcauseofinstabilityinaplaqueleadingtoanacuteischaemicevent.isstress/strainwithinthearterialwallmayrepre-sentthemostimportantfactorforatherosclerosiswiththeotherwell-knownriskfactorsrepresentingacceleratorsofatherosclerosis[4.SummaryandConclusionInsummary,thereisincreasingevidenceshowingtheassoci-ationbetweenthedistributionanddensityofvasavasoruminthearterialwallandseverityofplaqueformation,aswellasthedevelopmentofatherosclerosis.However,furtherstudiesareneededtoclarifywhetherthevasavasorumplayacausativeoronlyreactiveroleintheatherogenesis.Variousimagingmodalitiesareusednotonlytodemon-stratenormalanatomyofvasavasorum,butalsocharac-terizethecomposition,burdenandneovascularizationofatheroscleroticplaqueassociatedwithvasavasoruminjury.iswillbediscussedinthepaperofimagingmodalitiesinthevisualizationofvasavasorumandatheroscleroticplaque.ConflictofInterestseauthordeclaresthatthereisnoconictofinterestsregardingthepublicationofthispaper.[]A.C.BargerandR.BeeuwkesIII,Ruptureofcoronaryvasavasorumasatriggerofacutemyocardialinfarction,AmericanJournalofCardiology,vol. ,no. ,pp.G G,.[]F.D.Mann,Vasavasorumandcoronaryatherosclerosis,Lancet,vol.,no.,pp. ,.[]H.M.Kwon,G.Sangiorgi,E.L.Ritmanetal.,Adventitialvasavasoruminballoon-injuredcoronaryarteries:visualizationandquantitationbyamicroscopicthree-dimensionalcomputedtomographytechnique,JournaloftheAmericanCollegeofCardiology,vol.,no.,pp. ,.[]J.-I.Sanada,O.Matsui,J.Yoshikawa,andT.Matsuoka,Anexperimentalstudyofendovascularstentingwithspecialrefer-encetothee ectsontheaorticvasavasorum,CardiovascularandInterventionalRadiology,vol.,no.,pp. ,.[ ]J.Herrmann,L.O.Lerman,M.Rodriguez-Porceletal.,Coronaryvasavasorumneovascularizationprecedesepi-cardialendothelialdysfunctioninexperimentalhypercholes-terolemia,CardiovascularResearch,vol. ,no.,pp. ,.[ ]J.Herrmann,P.J.Best,E.L.Ritman,D.R.HolmesJr.,L.O.Lerman,andA.Lerman,Chronicendothelinreceptorantag-onismprevents:coronaryvasavasorumneovascularizationinexperimentalhypercholesterolemia,JournaloftheAmericanCollegeofCardiology,vol.,no.,pp. ,.[]M.Slevin,L.Badimon,M.Grau-Olivaresetal.,Combiningnanotechnologywithcurrentbiomedicalknowledgeforthevascularimagingandtreatmentofatherosclerosis,MolecularBioSystems,vol. ,no.,pp. ,.[]R.Ross,epathogenesisofatherosclerosis:aperspectiveforthes,Nature,vol. ,no. ,pp. ,.[]I.M.vanderMeer,A.I.DelSol,A.E.Hak,M.L.Bots,A.Hofman,andJ.C.M.Witteman,Riskfactorsforprogressionofatherosclerosismeasuredatmultiplesitesinthearterialtree:theRotterdamstudy,Stroke,vol.,no.,pp. ,.[]A.KarandT.Glasz,Developmentofatherosclerosisandplaquebiology,CardiovascularSurgery,vol.,no.,pp. ,.[]A.C.vanderWal,A.E.Becker,C.M.vanderLoos,andP.K.Das,Siteofintimalruptureorerosionofthrombosedcoronaryatheroscleroticplaquesischaracterizedbyaninammatoryp
rocessirrespectiveofthedominantplaquemorphology,Circulation,vol.,no.,pp. ,.[]R.Mo di,T.B.Crotty,P.McCarthy,S.J.Sheehan,D.Mehigan,andT.V.Keaveny,Associationbetweenplaqueinstability,angiogenesisandsymptomaticcarotidocclusivedisease,BritishJournalofSurgery,vol.,no.,pp. ,.[]K.S.Moulton,E.Heller,M.A.Konerding,E.Flynn,W.Palinski,andJ.Folkman,AngiogenesisinhibitorsendostatinorTNP-reduceintimalneovascularizationandplaquegrowthinapolipoproteinE-de cientmice,Circulation,vol.,no.,pp. ,.[]A.N.Tenaglia,K.G.Peters,J.SketchM.H.,andB.H.Annex,Neovascularizationinatherectomyspecimensfrompatientswithunstableangina:implicationsforpathogenesisofunstableangina, eAmericanHeartJournal,vol. ,no.,pp. ,.[ ]E.R.OBrien,M.R.Garvin,R.Devetal.,Angiogenesisinhumancoronaryatheroscleroticplaques, eAmericanJournalofPathology,vol. ,no.,pp. ,.[ ]M.J.McCarthy,I.M.Lo us,M.M.ompsonetal.,Angio-genesisandtheatheroscleroticcarotidplaque:anassociationbetweensymptomatologyandplaquemorphology,JournalofVascularSurgery,vol.,no.,pp. ,.[]R.Khurana,Z.Zhuang,S.Bhardwajetal.,Angiogenesis-dependentandindependentphasesofintimalhyperplasia,Circulation,vol.,no. ,pp. ,.[]E.Geiringer,Intimalvascularizationandatherosclerosis,JournalofPathologyandBacteriology,vol. ,no.,pp. , .[]H.WolinskyandS.Glagov,Natureofspeciesdi erencesinthemedialdistributionofaorticvasavasoruminmammals,CirculationResearch,vol.,no.,pp. , . eScienti cWorldJournal[]K.Okuyama,G.-Y.Yaginuma,T.Takahashi,H.Sasaki,andS.Mori,edevelopmentofvasavasorumofthehumanaortainvariousconditions:amorphometricstudy,ArchivesofPathologyandLaboratoryMedicine,vol.,no.,pp. ,.[]C.A.Woerner,Vasavasoruminarteries,theirdemonstrationanddistribution,in eArterialWall,A.I.Lansing,Ed.,pp. ,WilliamsandWilkins,Baltimore,Md,USA, .[]M.Gossl,N.M.Malyar,M.Rosol,P.E.Beighley,andE.L.Ritman,Impactofcoronaryvasavasorumfunctionalstructureoncoronaryvesselwallperfusiondistribution, eAmericanJournalofPhysiology:HeartandCirculatoryPhysiology,vol. ,no. ,pp.H H ,.[]D.-G.Han,einnatenessofcoronaryartery:vasavasorum,MedicalHypotheses,vol.,no.,pp. ,.[]F.SchoenenbergerandA.Mueller,Ueberdievaskularisierungderrinderaortenwand,HelveticaPhysiologicaatPharmacolog-icaActa,vol.,pp. , .[ ]M.Gossl,M.Rosol,N.M.Malyaretal.,Functionalanatomyandhemodynamiccharacteristicsofvasavasoruminthewallsofporcinecoronaryarteries,AnatomicalRecordA:DiscoveriesinMolecular,Cellular,andEvolutionaryBiology,vol.,no.,pp. ,.[ ]O.Galili,J.Herrmann,J.Woodrum,K.J.Sattler,L.O.Lerman,andA.Lerman,Adventitialvasavasorumheterogeneityamongdi erentvascularbeds,JournalofVascularSurgery,vol.,no.,pp. ,.[]H.A.Hildebrandt,M.Gossl,D.Mannheimetal.,Di erentialdistributionofvasavasorumindi erentvascularbedsinhumans,Atherosclerosis,vol.,no.,pp. ,.[]E.L.RitmanandA.Lerman,edynamicvasavasorum,CardiovascularResearch,vol. ,no.,pp. ,.[]K.S.Moulton,K.Vakili,D.Zurakowskietal.,Inhibitionofplaqueneovascularizationreducesmacrophageaccumulationandprogressionofadvancedatherosclerosis,ProceedingsoftheNationalAcademyofSciencesoftheUnitedStatesofAmericavol.,no.,pp. ,.[]W.Koester,Endarteritisandarteritis,BerlineKlinischeWochenschri ,vol.,pp. , .[]A.C.Winternitz,R.M.omas,andP.M.LeCompte,BiologyofArteriosclerosis,CharlesComas,Spring eld,Ill,USA,.[]A.C.Barger,R.BeeuwkesIII,L.L.Lainey,andK.J.Silverman,Hypothesis:vasavasorumandneovascularizationofhumancoronaryarteries:apossibleroleinthepathophysiologyofatherosclerosis, e
NewEnglandJournalofMedicine,vol.,no.,pp. ,.[]K.MaiellaroandW.R.Taylor,eroleoftheadventitiainvascularinammation,CardiovascularResearch,vol. ,no.,pp. ,.[]J.N.Wilcox,R.Waksman,S.B.King,andN.A.Scott,eroleoftheadventitiainthearterialresponsetoangioplasty:thee ectofintravascularradiation,InternationalJournalofRadiationOncologyBiologyPhysics,vol. ,no.,pp. , .[ ]Y.Shi,J.E.OBrienJr.,A.Fard,J.D.Mannion,D.Wang,andA.Zalewski,Adventitialmyo broblastscontributetoneointimalformationininjuredporcinecoronaryarteries,Circulation,vol.,no.,pp. , .[ ]L.Zhao,M.P.W.Moos,R.Grabneretal.,e -lipoxygenasepathwaypromotespathogenesisofhyperlipidemiadependen-taorticaneurysm,NatureMedicine,vol.,pp. ,.[]S.H.Wilson,J.Herrmann,L.O.Lermanetal.,Simvastatinpreservesthestructureofcoronaryadventitialvasavasoruminexperimentalhypercholesterolemiaindependentoflipidlowering,Circulation,vol. ,no.,pp. ,.[]C.M.Bloor,F.C.White,andD.M.Roth,epigasamodelofmyocardialischemiaandgradualcoronaryarteryocclusion,SwineasModelsinBiomedicalResearch,M.M.Swindle,MoodyDC,andL.D.Phillips,Eds.,pp. ,IowaStateUniversityPress,Ames,Iowa,USA,.[]F.D.Kolodgie,H.K.Gold,A.P.Burkeetal.,Intraplaquehemorrhageandprogressionofcoronaryatheroma, eNewEnglandJournalofMedicine,vol.,no.,pp. ,.[]M.Gossl,D.Versari,H.A.Hildebrandtetal.,Segmentalheterogeneityofvasavasorumneovascularizationinhumancoronaryatherosclerosis,JACC:CardiovascularImaging,vol.,no.,pp. ,.[]M.Gossl,D.Versari,D.Mannheim,E.L.Ritman,L.O.Lerman,andA.Lerman,IncreasedspatialvasavasorumdensityintheproximalLADinhypercholesterolemia-Implicationsforvulnerableplaque-development,Atherosclerosis,vol.,no.,pp. ,.[]P.R.Moreno,K.R.Purushothaman,V.Fusteretal.,Plaqueneovascularizationisincreasedinrupturedatheroscleroticlesionsofhumanaorta:implicationsforplaquevulnerability,Circulation,vol.,no.,pp. ,.[]B.Kou,J.Zhang,andD.R.J.Singer,E ectsofcyclicstrainonendothelialcellapoptosisandtubulogenesisaredependentonROSproductionviaNAD(P)Hsubunitpphox,Microvascu-larResearch,vol.,no.,pp. ,.[]D.Morrow,J.P.Cullen,P.A.Cahill,andE.M.Redmond,CyclicstrainregulatestheNotch/CBF-signalingpathwayinendothelialcells:roleinangiogenicactivity,Arteriosclerosis, rombosis,andVascularBiology,vol.,no. ,pp. ,.[ ]T.Idzenga,G.Pasterkamp,andC.L.deKorte,Shearstrainintheadventitiallayerofthearterialwallfacilitatesdevelopmentofvulnerableplaques,BioscienceHypotheses,vol.,no. ,pp. ,.[ ]E.L.Schi rin,Vascularsti eningandarterialcompliance:implicationsforsystolicbloodpressure, eAmericanJournalofHypertension,vol.,no.,pp.S S,.[]K.T.Nguyen,C.D.Clark,T.J.Chancellor,andD.V.Papavas-siliou,Carotidgeometrye ectsonbloodowandonriskforvasculardisease,JournalofBiomechanics,vol.,no.,pp. ,.[]J.B.omas,L.Antiga,S.L.Cheetal.,Variationinthecarotidbifurcationgeometryofyoungversusolderadults:implicationsforgeometricriskofatherosclerosis,Stroke,vol. ,no.,pp. , .[]I.Marshall,S.Zhao,P.Papathanasopoulou,P.Hoskins,andX.Y.Xu,MRIandCFDstudiesofpulsatileowinhealthyandstenosedcarotidbifurcationmodels,JournalofBiomechanicsvol.,no. ,pp. ,.[ ]D.Birchall,A.Zaman,J.Hacker,G.Davies,andD.Mendelow,Analysisofhaemodynamicdisturbanceintheatheroscleroticcarotidarteryusingcomputationaluiddynamics,EuropeanRadiology,vol. ,no. ,pp. , .[ ]M.Lawrence-Brown,B.M.Stanley,Z.Sun,J.B.Semmens,andK.Li man,Stressandstrainbehaviourmodellingofthecarotidbifurcation,ANZJournalofSurgery,vol.,no.,pp. ,. Submit your manuscripts athttp://www.hindaw