producthaole008.com
haole008.com 时间:2021-04-08 阅读:()
REVIEWwww.
nature.
com/clinicalpractice/nephMechanismsofDisease:pre-eclampsiaMarinaNoris*,NorbertoPericoandGiuseppeRemuzziThisarticleofferstheopportunitytoearnoneCategory1credittowardstheAMAPhysician'sRecognitionAward.
INTRODUCTIONPre-eclampsiaisasyndromethatisusuallydefinedastheonsetofhypertensionandproteinuriaafter20weeksofgestationinprevi-ouslynormotensivenon-proteinuricpreg-nantwomen.
1Ifleftuntreated,pre-eclampsiacanprogresstoaconvulsivestateknownaseclampsia.
2Pre-eclampsiaisaleadingcauseofmaternalandfetalmorbidityandmortality.
3,4IntheWesternworld,itaffectsbetween2and7%ofallpregnancies,buttheincidenceinothergeographicareaswithdifferentethnicorsocialcharacteristicscanbeuptothreetimesgreater.
5,6Aworldwideincidenceof8,370,000casesperyearhasbeenestimated.
5,6Indevelopingcoun-tries,suchasColombia,42%ofmaternaldeathsareattributedtothisdisorder,whichisalsothemajorreasonforprematuredelivery.
7Theinci-denceofeclampsiaisalsohighindevelopingcountries(1.
6and12per1,000livebirths,respectively,inColombiaandIndia).
8RISKFACTORSPre-eclampsiaisprimarilyregardedasadiseaseoffirstpregnancy,althoughtheprotectiveeffectofmultiparityissaidtobelostwithchangeofpartner.
9Thissupportsthehypothesisthatriskisreducedwithrepeatedexposurestospecificantigensfromthesamepartner;however,recentevidencefromtheMedicalBirthRegistryofNorwayindicatesthattheprotectiveeffectofpreviouspregnancywiththesamepartnerisconfoundedbythetimeintervalbetweenbirths.
10Thesedata,obtainedfrom>1.
8millionbirthsover31years,showedthatwhenthebirthintervalwas>10years,amultiparouswomanhadthesameriskofdevelopingpre-eclampsiaasaprimiparouswoman.
Ithas,however,beensuggestedthatthis'birth-intervalhypothesis'isnotwellfounded.
11Asystematicreviewof>1,000controlledstudiespublishedfrom1966to2002foundthatPre-eclampsia,asyndromeofpregnantwomen,isoneoftheleadingcausesofmaternalandfetalmorbidityandmortality.
Despiteactiveresearch,theetiologyofthisdisorderremainsanenigma.
Recentworkhas,however,providedpromisingexplanationsforthecausationofthedisorderandsomeofitsphenotypes.
Evidenceindicatesthatthesymptomsofhypertensionandproteinuria,uponwhichthediagnosisofpre-eclampsiaisbased,haveseveralunderlyingcauses.
Nevertheless,thetreatmentofpre-eclampsiahasnotchangedsignificantlyinover50years.
Thisreviewdescribesthemostrecentinsightsintothepathophysiologyofpre-eclampsiafrombothbasicandclinicalresearch,andattemptstoprovideaunifyinghypothesistoreconciletheabnormalitiesatthefeto–placentallevelandtheclinicalfeaturesofthematernalsyndrome.
Thenovelfindingsoutlinedinthisreviewprovidearationaleforpotentialfutureprophylacticandtherapeuticinterventionsforpre-eclampsia.
KEYWORDSnitricoxide,oxygenradicals,pathophysiology,pre-eclampsia,vascularendothelialgrowthfactorMNorisisHeadoftheLaboratoryofImmunologyandGeneticsofTransplantationandRareDiseases,NPericoisHeadoftheLaboratoryofAdvancedDevelopmentofDrugsattheClinicalResearchCenterforRareDiseasesandGRemuzziisDirectoroftheClinicalResearchCenterforRareDiseases,atMarioNegriInstituteforPharmacologicalResearch,Bergamo,Italy.
Correspondence*TransplantResearchCenter"ChiaraCucchiDeAlessandri&GilbertoCrespi",MarioNegriInstituteforPharmacologicalResearch,ViaCamozzi3,24020Ranica,Bergamo,Italynoris@marionegri.
itReceived27April2005Accepted25August2005www.
nature.
com/clinicalpracticedoi:10.
1038/ncpneph0035REVIEWCRITERIAWesearchedPubMedforarticlespublishedbetween1970and2005.
Thekeywordsusedwere"pre-eclampsia","gestationalhypertension","clinicalfeatures","pathophysiology"and"treatment".
Wealsosearchedthebibliographiesofthearticlesretrievedforfurtherrelevantreferences.
Becauseofthelargenumberofarticlesidentified,thedecisiononwhichtoincludewasbasedonpersonaljudgment.
Moreover,asthediagnosticcriteriaforpre-eclampsiawererefinedin2000bytheNationalHighBloodPressureEducationProgramWorkingGroup,1thisreviewfocusesonstudiespublishedduringthepast5years.
SUMMARYCME98NATURECLINICALPRACTICENEPHROLOGYDECEMBER2005VOL1NO2NaturePublishingGroup2005REVIEWDECEMBER2005VOL1NO2NORISETAL.
NATURECLINICALPRACTICENEPHROLOGY99www.
nature.
com/clinicalpractice/nephaprevioushistoryofpre-eclampsia,multiplepregnancy,nulliparity,pre-existingdiabetes,highBMIbeforepregnancy,maternalage≥40years,renaldisease,hypertension,≥10yearssincepreviouspregnancyandpresenceofanti-phospholipidantibodiesallincreasedawoman'sriskofdevelopingpre-eclampsia.
12Increasesinriskofmorethanninefold,sevenfoldandthreefold,respectively,weredocumentedforantiphospholipidantibodies,previoushistoryofpre-eclampsiaanddiabetes.
Basedonthisevidence,guidelinesforriskassessmentofpre-eclampsiahaverecentlybeenissued.
13Otherriskfactorsforpre-eclampsiaareinsulinresistanceinconcertwithobesity14,15andthrombophilia.
16Indevelopingcountries,protein-calorieundernutritionhasbeenidentifiedasanimportantriskfactor;17however,anegativecorrelationbetweencalciumintakeandincidenceofpre-eclampsiahasrecentlybeendetectedinGuatemala,ColombiaandIndia.
7Thisfindingissupportedbytheobservationthatcalciumsupple-mentationisbeneficialtowomenathighriskofgestationalhypertension,andincommunitieswithlowdietarycalciumintake.
18–20GeneticfactorsThepreciseroleofgeneticfactorsinthedevelop-mentofpre-eclampsiaisunclear,andnospecificcontributorygenehasbeenidentified.
Theinheri-tancepatternofthediseasehasbeendescribedasMendelian(autosomalrecessiveandauto-somaldominantwithincompletepenetrance),polygenic/multifactorialandmitochondrial.
Smallstudies21–24haveindicatedanassociationbetweenpre-eclampsiaandpolymorphismsofgenesthatcontrolbloodpressure,coagulationoroxygen-free-radicalmetabolism—suchasrenin,angiotensinogen,endothelialnitricoxidesynthase(eNOS),FACTORVLEIDEN,METHYLTETRAHYDROFOLATEorlipoproteinlipase—butthishasnotbeenconfirmed.
25Linkageanalysishasidentifiedthreepotentiallocilinkedtosusceptibilitytopre-eclampsia:2p13,2p25and9p13.
26,27Notably,theselociaccountforonlyasmallpercentageofcases(otherstudiesfailedtoconfirmtheassociations).
28,29Afourthlocusforpre-eclampsiawassubsequentlyidenti-fiedon10q22.
Maximalallelesharingbetweenpre-eclampticsistersatthislocuswasobservedformaternal-derivedbutnotpaternal-derivedalleles,30indicatingmatrilinealinheritance.
TheSTOX1geneinthe10q22locuscontainsfivedifferentmissensemutations.
STOX1isidenticalinaffectedsisters,co-segregateswiththepre-eclampticphenotypeandisinheritedmatrilineally.
31Arolehasbeenproposedforthegeneproduct(aDNA-bindingprotein)incontrollingpolyploidizationofextravilloustrophoblasts,althoughitsprecisebiologicalfunctionhasnotbeenclarified.
31InalargestudybytheBritishGeneticsofPre-eclampsiaConsortium,657womenaffectedbypre-eclampsiaandtheirfamiliesweregenotypedatsitesof28single-nucleotidepolymorphismsinseveralgenes,includingthoseinvolvedinangiotensinactivity(angiotensinogenandangiotensinIItype1receptor[AT1])andoxida-tivestress(methylenetetrahydrofolatereduc-tase).
32Noneofthegeneticvariantstestedwerefoundtoconferahighriskofdiseasedevelop-ment,indicatingthatalterationsofangiotensinactivityandoxidativestressarenotprimecausesofpre-eclampsia.
DIAGNOSISANDCLINICALFEATURESThecardinalfeaturesofpre-eclampsiaarehypertensionandproteinuria.
Inthepast,hyper-tensionindicativeofpre-eclampsiawasdefinedasanelevationof>30mmHgsystolicpressureor>15mmHgdiastolicpressureabovethepatient'sbaselinebloodpressure.
Thisdefinitionprovedtobeapoorindicatorofoutcome33and,in2000,thecriteriawererefinedbytheNationalHighBloodPressureEducationProgram(NHBPEP)WorkingGroup.
1Sincethen,therehasbeenconsiderableagreementbetweeninternationalworkinggroups.
34Thecriteriadefinehyper-tensionasasystolicbloodpressure≥140mmHgoradiastoliclevel(Korotkoff5)≥90mmHgontwoormoreoccasionsatleast4–6h(butnotmorethan7days)apartafter20weeksofgesta-tioninawomanwithpreviouslynormalbloodpressure.
Nevertheless,theNHBPEPworkinggroupreport1alsostatedthecollectiveopinionthat30mmHgsystolicand15mmHgdiastolicincreases,evenatvalues140mmHg,diastolicbloodpressure>90mmHg1Proteinuria:urinaryproteinexcretion>300mg/day;preservationofpodocytefootprocessesinthepresenceofsubstantialproteinuria137Decreasedplasmavolume:contractedby30–40%comparedwithnormalpregnancy138Edema:interstitialfluidretention;multifactorial138(observedin>50%ofnormalgravidas)Decreasedrenalbloodflow:renalperfusionlessthaninnormalpregnantwomen101Increasedplasmauricacid:secondarytoreduceduricacidrenalclearance139Increasedaminotransferasesandlactatedehydrogenase:hepatocellularnecrosiswithleakageofliverenzymesintomaternalblood140Cerebraledema:duetohypertensionandvascularautoregulatorydysfunction141Thrombocytopenia:plateletcount/=15mmHginassociationwithproteinuriaAmJObstetGynecol183:787–79234BrownMAetal.
(2001)Theclassificationanddiagnosisofthehypertensivedisordersofpregnancy:astatementfromtheInternationalSocietyfortheStudyofHypertensioninPregnancy(ISSHP).
HypertensPregn20:IX–XIV35WaughJJetal.
(2004)Accuracyofurinalysisdipsticktechniquesinpredictingsignificantproteinuriainpregnancy.
ObstetGynecol103:769–77736SibaiBM(2004)Diagnosis,controversies,andmanagementofHELLPsyndrome.
ObstetGynecol103:981–99137YamasmitWetal.
(2004)Randomurinaryprotein-to-creatinineratioforpredictionofsignificantproteinuriainwomenwithpreeclampsia.
JMaternFetalNeonatalMed16:275–27938BrownMAetal.
(2000)Thedetection,investigationandmanagementofhypertensioninpregnancy:executivesummary.
AustNZJObstetGynecol40:133–13839SibaiBM(2002)Chronichypertensioninpregnancy.
ObstetGynecol100:369–37740GilstrapLCIIIandRaminSMonbehalfoftheACOGCommitteeonPracticeBulletin(2002)Diagnosisandmanagementofpreeclampsiaandeclampsia.
IntJObstetGynecol77:67–7541MoranPetal.
(2004)Therenalresponsetopreeclampsia.
SeminNephrol24:588–59542HibbardJUetal.
(2004)Cardiovascularchangesinpreeclampsia.
SeminNephrol24:580–58743HaukkamaaLetal.
(2004)Riskforsubsequentcoronaryarterydiseaseafterpreeclampsia.
AmJCardiol93:805–808NaturePublishingGroup2005REVIEW112NATURECLINICALPRACTICENEPHROLOGYNORISETAL.
DECEMBER2005VOL1NO2www.
nature.
com/clinicalpractice/neph44ZhangJetal.
(2003)SeverematernalmorbidityassociatedwithhypertensivedisordersinpregnancyintheUnitedStates.
HypertensPregn22:203–21245HauthJCetal.
(2000)Pregnancyoutcomesinhealthynulliparouswomenwhosubsequentlydevelopedhypertension.
ObstetGynecol95:24–2846BuchbinderAetal.
(2002)Adverseperinataloutcomesaresignificantlyhigherinseveregestationalhypertensionthaninmildpreeclampsia.
AmJObstetGynecol186:66–7147DuleyL(2003)Pre-eclampsiaandthehypertensivedisordersofpregnancy.
BrMedBull67:161–17648Conde-AgudeloAetal.
(2004)WorldHealthOrganizationsystematicreviewofscreeningtestsforpreeclampsia.
ObstetGynecol104:1367–139149NorthRA(2003)Canwepredictpre-eclampsiaInPreeclampsia,257–275(EdsCritchleyHetal.
)London:RCOGPress50Axt-FliednerR(2004)SecondtrimesteruterinearteryDopplerultrasoundasascreeningtestforadversepregnancyoutcome.
ClinExpObstetGynecol31:9–1151Red-HorseKetal.
(2004)Trophoblastdifferentiationduringembryoimplantationandformationofthematernal–fetalinterface.
JClinInvest114:744–75452LyallF(2005)Primingandremodellingofhumanplacentalbedspiralarteriesduringpregnancy—areview.
Placenta26(SupplA):S31–S3653ZhouYetal.
(1997)Preeclampsiaisassociatedwithfailureofhumancytotrophoblaststomimicavascularadhesionphenotype:OnecauseofdefectiveendovascularinvasioninthissyndromeJClinInvest99:2152–216454PijnenborgRetal.
(1991)Placentalbedspiralarteriesinthehypertensivedisordersofpregnancy.
BrJObstetGynaecol98:648–65555KadyrovMetal.
(2003)Preeclampsiaandmaternalanemiadisplayreducedapoptosisandoppositeinvasivephenotypesofextravilloustrophoblast.
Placenta24:540–54856MoldenhauerJSetal.
(2003)Thefrequencyandseverityofplacentalfindingsinwomenwithpreeclampsiaaregestationalagedependent.
AmJObstetGynecol189:1173–117757TeasdaleF(1985)Histomorphometryofthehumanplacentainmaternalpreeclampsia.
AmJObstetGynecol152:25–3158Moffett-KingA(2002)Naturalkillercellsandpregnancy.
NatRevImmunol2:656–66359ParhamP(2004)NKcellsandtrophoblasts:partnersinpregnancy.
JExpMed200:951–95560HibySEetal.
(2004)CombinationsofmaternalKIRandfetalHLA-Cgenesinfluencetheriskofpreeclampsiaandreproductivesuccess.
JExpMed200:957–96561ZhouYetal.
(1997)Humancytotrophoblastsadoptavascularphenotypeastheydifferentiate.
AstrategyforsuccessfulendovascularinvasionJClinInvest99:2139–215162SharkeyAetal.
(1993)Expressionofvascularendothelialgrowthfactorinhumanplacenta.
JReprodFertil99:609–61563ZhouYetal.
(2002)Vascularendothelialgrowthfactorligandsandreceptorsthatregulatehumancytotrophoblastsurvivalaredysregulatedinseverepreeclampsiaandhemolysis,elevatedliverenzymes,andlowplateletssyndrome.
AmJPathol160:1405–142364CooperJetal.
(1996)VEGFmRNAlevelsinplacentaefrompregnanciescomplicatedbypreeclampsia.
BrJObstetGynaecol103:1191–119665LevineRetal.
(2004)Circulatingangiogenicfactorsandtheriskofpreeclampsia.
NEnglJMed350:672–68366MaynardSetal.
(2003)Excessplacentalsolublefms-liketyrosinekinase1(sFlt1)maycontributetoendothelialdysfunction,hypertension,andproteinuriainpreeclampsia.
JClinInvest111:649–65867HirashimaMetal.
(2003)Trophoblastexpressionoffms-liketyrosinekinase1isnotrequiredfortheestablishmentofthematernal-fetalinterfaceinthemouseplacenta.
ProcNatlAcadSciUSA100:15637–1564268PapapetropoulosAetal.
(1997)Nitricoxideproductioncontributestotheangiogenicpropertiesofvascularendothelialgrowthfactorinhumanendothelialcells.
JClinInvest100:3131–313969MoncadaSandHiggsA(1993)TheL-arginine-nitricoxidepathway.
NEnglJMed329:2002–201270BaylisCetal.
(1998)Recentinsightsintotherolesofnitricoxideandrenin-angiotensininthepathophysiologyofpreeclampticpregnancy.
SeminNephrol18:208–23071ThomsonAJetal.
(1997)Nitricoxidesynthaseactivityandlocalizationdonotchangeinuterusandplacentaduringhumanparturition.
HumReprod12:2546–255272MartinDandConradKP(2000)Expressionofendothelialnitricoxidesynthasebyextravilloustrophoblastcellsinthehumanplacenta.
Placenta21:23–3173EisALetal.
(1995)Immunohistochemicallocalizationofendothelialnitricoxidesynthaseinhumanvillousandextravilloustrophoblastpopulationsandexpressionduringsyncytiotrophoblastformationinvitro.
Placenta16:113–12674OrangeSJetal.
(2003)Placentalendothelialnitricoxidesynthaselocalizationandexpressioninnormalhumanpregnancyandpre-eclampsia.
ClinExpPharmacolPhysiol30:376–38175LyallFetal.
(1999)Humantrophoblastinvasionandspiralarterytransformation.
Theroleofnitricoxide.
AmJPathol154:1105–111476NovaroVetal.
(2001)Regulationofmetalloproteinasesbynitricoxideinhumantrophoblastcellsinculture.
ReprodFertilDev13:411–42077DavisonJMetal.
(2004)Newaspectsinthepathophysiologyofpreeclampsia.
JAmSocNephrol15:2440–244878DunkCetal.
(2000)Angiopoietin-1andangiopoietin-2activatetrophoblastTie-2topromotegrowthandmigrationduringplacentaldevelopment.
AmJPathol156:2185–219979AhmedAetal.
(1997)RoleofVEGFreceptor-1(Flt-1)inmediatingcalcium-dependentnitricoxidereleaseandlimitingDNAsynthesisinhumantrophoblastcells.
LabInvest76:779–79180ChangCCetal.
(2005)InductionofVE-cadherininratplacentaltrophoblastsbyVEGFthroughaNO-dependentpathway.
Placenta26:234–24181NorisMetal.
(1996)Theroleofvasoactivemoleculesofendothelialorigininthepathophysiologyofnormalpregnancyandpregnancy-inducedhypertension.
CurrOpinNephrolHypertens5:347–35282RadiRetal.
(1991)Peroxynitrite-inducedmembranelipidperoxidation:thecytotoxicpotentialofsuperoxideandnitricoxide.
ArchBiochemBiophys288:481–48783ManyAetal.
(2000)Invasivecytotrophoblastsmanifestevidenceofoxidativestressinpreeclampsia.
AmJPathol156:321–33184WangWetal.
(2000)Superoxideproductionandreactiveoxygenspeciessignalingbyendothelialnitric-oxidesynthase.
JBiolChem275:16899–16903NaturePublishingGroup2005REVIEWDECEMBER2005VOL1NO2NORISETAL.
NATURECLINICALPRACTICENEPHROLOGY113www.
nature.
com/clinicalpractice/neph85XiaYetal.
(1996)Nitricoxidesynthasegeneratessuperoxideandnitricoxideinarginine-depletedcellsleadingtoperoxynitrite-mediatedcellularinjury.
ProcNatlAcadSciUSA93:6770–677486Vasquez-VivarJetal.
(1998)Superoxidegenerationbyendothelialnitricoxidesynthase:theinfluenceofcofactors.
ProcNatlAcadSciUSA95:9220–922587XiaYandZweierJL(1997)Superoxideandperoxynitritegenerationfrominduciblenitricoxidesynthaseinmacrophages.
ProcNatlAcadSciUSA94:6954–695888NorisMetal.
(2004)L-argininedepletioninpreeclampsiaorientsnitricoxidesynthasetowardoxidantspecies.
Hypertension43:614–62289LiHetal.
(2001)RegulatoryroleofarginaseIandIIinnitricoxide,polyamine,andprolinesynthasesinendothelialcells.
AmJPhysiol280:E75–E8290LoweD(2000)Nitricoxidedysfunctioninthepathophysiologyofpreeclampsia.
NitricOxide4:441–45891CarlsenSMetal.
(2005)Earlysecond-trimestermaternalhyperandrogenemiaandsubsequentpreeclampsia:aprospectivestudy.
ActaObstetGynecolScand84:117–12192GermainAetal.
(2004)EvidencesupportingabeneficialroleforlongtermL-argininesupplementationinhighriskpregnancies.
Hypertension44:e193MolnarMetal.
(1994)Prolongedblockadeofnitricoxidesynthesisingravidratsproducessustainedhypertension,proteinuria,thrombocytopenia,andintrauterinegrowthretardation.
AmJObstetGynecol170:1458–146694TanirHMetal.
(2005)Effectofquercetineandglutathioneonthelevelofsuperoxidedismutase,catalase,malonyldialdehyde,bloodpressureandneonataloutcomeinaratmodelofpre-eclampsiainducedbyNG-nitro-L-arginine-methylester.
EurJObstetGynecolReprodBiol118:190–19595CaniggiaIandWinterJL(2002)Hypoxiainduciblefactor-1:oxygenregulationoftrophoblastdifferentiationinnormalandpre-eclampticpregnancies—Areview.
Placenta23(SupplA):S47–S5796RajakumarAetal.
(2004)Evidenceofthefunctionalactivityofhypoxia-inducibletranscriptionfactorsoverexpressedinpreeclampticplacentae.
Placenta25:763–76997CaniggiaIetal.
(2000)Hypoxia-induciblefactor-1mediatesbiologicaleffectsofoxygeninhumantrophoblastdifferentiationthroughTGFβ3.
JClinInvest105:577–58798CaniggiaIetal.
(1999)InhibitionofTGFβ3restorestheinvasivecapabilityofextravilloustrophoblastinpreeclampticpregnancies.
JClinInvest103:1641–165099HungT-Hetal.
(2002)Hypoxia-reoxygenation.
Apotentinducerofapoptoticchangesinthehumanplacentaandpossibleetiologicalfactorinpreeclampsia.
CircRes90:1274–1281100ParksDetal.
(1988)Conversionofxanthinedehydrogenasetooxidaseinischemicratintestine:areevaluation.
AmJPhysiol254:G768–G774101McLaughlinMKandRobertsJM(1999)Hemodynamicchangesinpregnancy.
InHypertensiveDisordersinPregnancy,92–95(EdsLindheimerMDetal.
)Stamford:Appleton&Lange102ShahD(2005)Roleoftherenin–angiotensinsysteminthepathogenesisofpreeclampsia.
AmJRenalPhysiol288:F614–F625103BowyerLetal.
(2003)Forearmbloodflowinpre-eclampsia.
BJOG110:383–391104ElsheikhAetal.
(2001)Therenin-aldosteronesystemduringnormalandhypertensivepregnancy.
ArchGynecolObstet264:182–185105WalshS(2004)Eicosanoidsinpreeclampsia.
ProstaglandinsLeukotEssentFattyAcids70:223–232106SeligmanSPetal.
(1994)Theroleofnitricoxideinthepathogenesisofpreeclampsia.
AmJObstetGynecol171:944–948107GarmendiaJVetal.
(1997)Nitricoxideindifferenttypesofhypertensionduringpregnancy.
ClinSci93:413–421108FicklingSAetal.
(1993)Plasmaconcentrationsofendogenousinhibitorofnitricoxidesynthesisinnormalpregnancyandpre-eclampsia.
Lancet34:242–243109Lopez-JaramilloPetal.
(1996)Cyclicguanosidine3,5monophosphateconcentrationsinpre-eclampsia:effectsofhydralazine.
BrJObstetGynaecol103:33–38110PridjianGandPuschettJB(2002)Preeclampsia.
Part1:Clinicalandpathophysiologicconsiderations.
ObstetGynecolSurv57:598–618111BuhimschiCSetal.
(2005)Urinaryangiogenicfactorsclusterhypertensivedisordersandidentifywomenwithseverepreeclampsia.
AmJObstetGynecol192:734–741112StepanHetal.
(2004)Solublefms-liketyrosinekinase1.
NEnglJMed351:2241–2242113WolfMetal.
(2005)CirculatinglevelsoftheantiangiogenicmarkersFLT-1areincreasedinfirstversussecondpregnancies.
AmJObstetGynecol193:16–22114LuttunAandCarmelietP(2003)SolubleVEGFreceptorFlt1:theelusivepreeclampsiafactordiscoveredJClinInvest111:600–602115LiHetal.
(2005)Hypoxia-inducedincreaseinsolubleFlt-1productioncorrelateswithenhancedoxidativestressintrophoblastcellsfromthehumanplacenta.
Placenta26:210–217116LivingstonJCetal.
(2000)Reductionsofvascularendothelialgrowthfactorandplacentalgrowthfactorconcentrationsinseverepreeclampsia.
AmJObstetGynecol183:1554–1557117LevineRJetal.
(2005)Urinaryplacentalgrowthfactorandriskofpreeclampsia.
JAMA293:77–85118MasudaYetal.
(2001)Vascularendothelialgrowthfactorenhancesglomerularcapillaryrepairandacceleratesresolutionofexperimentallyinducedglomerulonephritis.
AmJPathol159:599–608119SugimotoHetal.
(2003)Neutralizationofcirculatingvascularendothelialgrowthfactor(VEGF)byanti-VEGFantibodiesandsolubleVEGFreceptor1(sFlt-1)inducesproteinuria.
JBiolChem278:12605–12608120YangJetal.
(2003)Arandomizedtrialofbevacizumab,ananti-vascularendothelialgrowthfactorantibody,formetastaticrenalcancer.
NEnglJMed349:427–434121EreminaVetal.
(2003)Glomerular-specificalterationsofVEGF-Aexpressionleadtodistinctcongenitalandacquiredrenaldiseases.
JClinInvest111:707–716122BoydPetal.
(1987)Pre-eclampsiaandtrisomy13:apossibleassociation.
Lancet2:425–427123BdolahYetal.
(2005)Trisomy13andpreeclampsia:anoldlinkwithanewexplanation.
JSocGynecolInvest12(Suppl2):S196A124AbdAllaSetal.
(2001)IncreasedAT1receptorheterodimersinpreeclampsiamediateenhancedangiotensinIIresponsiveness.
NatMed7:1003–1009125DechendRetal.
(2000)AT(1)receptoragonisticantibodiesfrompreeclampticpatientscausevascularcellstoexpresstissuefactor.
Circulation101:2382–2387126BobstSMetal.
(2005)Maternalautoantibodiesfrompreeclampticpatientsactivateangiotensinreceptorsonhumanmesangialcellsandinduceinterleukin-6andplasminogenactivatorinhibitor-1secretion.
AmJHypertens18:330–336NaturePublishingGroup2005REVIEW114NATURECLINICALPRACTICENEPHROLOGYNORISETAL.
DECEMBER2005VOL1NO2www.
nature.
com/clinicalpractice/neph127XiaYetal.
(2003)Maternalautoantibodiesfrompreeclampticpatientsactivateangiotensinreceptorsonhumantrophoblastcells.
JSocGynecolInvestig10:82–93128HubelCetal.
(1989)Lipidperoxidationinpregnancy:Newperspectivesonpreeclampsia.
AmJObstetGynecol161:1025–1034129CosentinoFetal.
(2003)Highglucosecausesupregulationofcyclooxygenase-2andallprostanoidprofileinhumanendothelialcells:roleofproteinkinaseCandreactiveoxygenspecies.
Circulation107:1017–1023130ChappellLetal.
(1999)Effectofantioxidantsontheoccurrenceofpre-eclampsiainwomenatincreasedrisk:arandomizedtrial.
Lancet354:810–816131FacchinettiFetal.
(1999)L-Arginineinfusionreducesbloodpressureinpreeclampticwomenthroughnitricoxiderelease.
JSocGynecolInvest6:202–207132RytlewskiKetal.
(2005)EffectsofprolongedoralsupplementationwithL-arginineonbloodpressureandnitricoxidesynthesisinpreeclampsia.
EurJClinInvest35:32–37133ChappellLetal.
(2002)VitaminCandEsupplementationinwomenatriskofpreeclampsiaisassociatedwithchangesinindicesofoxidativestressandplacentalfunction.
AmJObstetGynecol187:777–784134RobertsJMandSpeerP(2004)Antioxidanttherapytopreventpreeclampsia.
SeminNephrol24:557–564135FraserWDetal.
(2005)ThevitaminEdebate:implicationsforongoingtrialsofpre-eclampsiaprevention.
BJOG112:684–688136SibaiBetal.
(2005)Pre-eclampsia.
Lancet365:785–799137MautnerWetal.
(1962)Preeclampticnephropathy.
Anelectronmicroscopicstudy.
LabInvest11:518–530138GalleryEandLindheimerM(1999)Pathologyandpathophysiologyofpreeclampsia:Alterationsinvolumehomeostasis.
InChesley'sHypertensiveDisordersinPregnancy,327–347(EdsLindheimerMetal.
)Stamford:Appleton&Lange139HayashiT(1956)Uricacidandendogenouscreatinineclearancestudiesinnormalpregnancyandtoxemiasofpregnancy.
AmJObstetGynecol71:859–870140ZissinRetal.
(1999)HepaticinfarctioninpreeclampsiaaspartoftheHELLPsyndrome:CTappearance.
AbdomImaging24:594–596141PortJandBeauchampNJ(1998)Reversibleintracerebralpathologicentitiesmediatedbyvascularautoregulatorydysfunction.
Radiographics18:353–367142SalehAetal.
(1992)Markersforendothelialinjury,clottingandplateletactivationinpreeclampsia.
ArchGynecolObstet251:105–110143StubbsTetal.
(1986)Evidenceofacceleratedplateletproductionandconsumptioninnonthrombocytopenicpreeclampsia.
AmJObstetGynecol155:263–265144LindheimerMD(2005)Unravelingthemysteriesofpreeclampsia.
AmJObstetGynecol193:3–4AcknowledgmentsWeareindebtedtoProfessorFranklinHEpstein(SeniorPhysician,RenalDivision,DepartmentofMedicine,BethIsraelDeaconessMedicalCenter,Boston)andWilliamApplebaum(ProfessorofMedicine,HarvardMedicalSchool,Boston)fortheircriticalreadingofthemanuscriptandinsightfuldiscussion.
WealsothankDrPrudenceHill(DepartmentofAnatomicalPathology,StVincent'sHospital,Melbourne)forhercriticalreading.
CompetinginterestsTheauthorsdeclaredtheyhavenocompetinginterests.
NaturePublishingGroup2005
nature.
com/clinicalpractice/nephMechanismsofDisease:pre-eclampsiaMarinaNoris*,NorbertoPericoandGiuseppeRemuzziThisarticleofferstheopportunitytoearnoneCategory1credittowardstheAMAPhysician'sRecognitionAward.
INTRODUCTIONPre-eclampsiaisasyndromethatisusuallydefinedastheonsetofhypertensionandproteinuriaafter20weeksofgestationinprevi-ouslynormotensivenon-proteinuricpreg-nantwomen.
1Ifleftuntreated,pre-eclampsiacanprogresstoaconvulsivestateknownaseclampsia.
2Pre-eclampsiaisaleadingcauseofmaternalandfetalmorbidityandmortality.
3,4IntheWesternworld,itaffectsbetween2and7%ofallpregnancies,buttheincidenceinothergeographicareaswithdifferentethnicorsocialcharacteristicscanbeuptothreetimesgreater.
5,6Aworldwideincidenceof8,370,000casesperyearhasbeenestimated.
5,6Indevelopingcoun-tries,suchasColombia,42%ofmaternaldeathsareattributedtothisdisorder,whichisalsothemajorreasonforprematuredelivery.
7Theinci-denceofeclampsiaisalsohighindevelopingcountries(1.
6and12per1,000livebirths,respectively,inColombiaandIndia).
8RISKFACTORSPre-eclampsiaisprimarilyregardedasadiseaseoffirstpregnancy,althoughtheprotectiveeffectofmultiparityissaidtobelostwithchangeofpartner.
9Thissupportsthehypothesisthatriskisreducedwithrepeatedexposurestospecificantigensfromthesamepartner;however,recentevidencefromtheMedicalBirthRegistryofNorwayindicatesthattheprotectiveeffectofpreviouspregnancywiththesamepartnerisconfoundedbythetimeintervalbetweenbirths.
10Thesedata,obtainedfrom>1.
8millionbirthsover31years,showedthatwhenthebirthintervalwas>10years,amultiparouswomanhadthesameriskofdevelopingpre-eclampsiaasaprimiparouswoman.
Ithas,however,beensuggestedthatthis'birth-intervalhypothesis'isnotwellfounded.
11Asystematicreviewof>1,000controlledstudiespublishedfrom1966to2002foundthatPre-eclampsia,asyndromeofpregnantwomen,isoneoftheleadingcausesofmaternalandfetalmorbidityandmortality.
Despiteactiveresearch,theetiologyofthisdisorderremainsanenigma.
Recentworkhas,however,providedpromisingexplanationsforthecausationofthedisorderandsomeofitsphenotypes.
Evidenceindicatesthatthesymptomsofhypertensionandproteinuria,uponwhichthediagnosisofpre-eclampsiaisbased,haveseveralunderlyingcauses.
Nevertheless,thetreatmentofpre-eclampsiahasnotchangedsignificantlyinover50years.
Thisreviewdescribesthemostrecentinsightsintothepathophysiologyofpre-eclampsiafrombothbasicandclinicalresearch,andattemptstoprovideaunifyinghypothesistoreconciletheabnormalitiesatthefeto–placentallevelandtheclinicalfeaturesofthematernalsyndrome.
Thenovelfindingsoutlinedinthisreviewprovidearationaleforpotentialfutureprophylacticandtherapeuticinterventionsforpre-eclampsia.
KEYWORDSnitricoxide,oxygenradicals,pathophysiology,pre-eclampsia,vascularendothelialgrowthfactorMNorisisHeadoftheLaboratoryofImmunologyandGeneticsofTransplantationandRareDiseases,NPericoisHeadoftheLaboratoryofAdvancedDevelopmentofDrugsattheClinicalResearchCenterforRareDiseasesandGRemuzziisDirectoroftheClinicalResearchCenterforRareDiseases,atMarioNegriInstituteforPharmacologicalResearch,Bergamo,Italy.
Correspondence*TransplantResearchCenter"ChiaraCucchiDeAlessandri&GilbertoCrespi",MarioNegriInstituteforPharmacologicalResearch,ViaCamozzi3,24020Ranica,Bergamo,Italynoris@marionegri.
itReceived27April2005Accepted25August2005www.
nature.
com/clinicalpracticedoi:10.
1038/ncpneph0035REVIEWCRITERIAWesearchedPubMedforarticlespublishedbetween1970and2005.
Thekeywordsusedwere"pre-eclampsia","gestationalhypertension","clinicalfeatures","pathophysiology"and"treatment".
Wealsosearchedthebibliographiesofthearticlesretrievedforfurtherrelevantreferences.
Becauseofthelargenumberofarticlesidentified,thedecisiononwhichtoincludewasbasedonpersonaljudgment.
Moreover,asthediagnosticcriteriaforpre-eclampsiawererefinedin2000bytheNationalHighBloodPressureEducationProgramWorkingGroup,1thisreviewfocusesonstudiespublishedduringthepast5years.
SUMMARYCME98NATURECLINICALPRACTICENEPHROLOGYDECEMBER2005VOL1NO2NaturePublishingGroup2005REVIEWDECEMBER2005VOL1NO2NORISETAL.
NATURECLINICALPRACTICENEPHROLOGY99www.
nature.
com/clinicalpractice/nephaprevioushistoryofpre-eclampsia,multiplepregnancy,nulliparity,pre-existingdiabetes,highBMIbeforepregnancy,maternalage≥40years,renaldisease,hypertension,≥10yearssincepreviouspregnancyandpresenceofanti-phospholipidantibodiesallincreasedawoman'sriskofdevelopingpre-eclampsia.
12Increasesinriskofmorethanninefold,sevenfoldandthreefold,respectively,weredocumentedforantiphospholipidantibodies,previoushistoryofpre-eclampsiaanddiabetes.
Basedonthisevidence,guidelinesforriskassessmentofpre-eclampsiahaverecentlybeenissued.
13Otherriskfactorsforpre-eclampsiaareinsulinresistanceinconcertwithobesity14,15andthrombophilia.
16Indevelopingcountries,protein-calorieundernutritionhasbeenidentifiedasanimportantriskfactor;17however,anegativecorrelationbetweencalciumintakeandincidenceofpre-eclampsiahasrecentlybeendetectedinGuatemala,ColombiaandIndia.
7Thisfindingissupportedbytheobservationthatcalciumsupple-mentationisbeneficialtowomenathighriskofgestationalhypertension,andincommunitieswithlowdietarycalciumintake.
18–20GeneticfactorsThepreciseroleofgeneticfactorsinthedevelop-mentofpre-eclampsiaisunclear,andnospecificcontributorygenehasbeenidentified.
Theinheri-tancepatternofthediseasehasbeendescribedasMendelian(autosomalrecessiveandauto-somaldominantwithincompletepenetrance),polygenic/multifactorialandmitochondrial.
Smallstudies21–24haveindicatedanassociationbetweenpre-eclampsiaandpolymorphismsofgenesthatcontrolbloodpressure,coagulationoroxygen-free-radicalmetabolism—suchasrenin,angiotensinogen,endothelialnitricoxidesynthase(eNOS),FACTORVLEIDEN,METHYLTETRAHYDROFOLATEorlipoproteinlipase—butthishasnotbeenconfirmed.
25Linkageanalysishasidentifiedthreepotentiallocilinkedtosusceptibilitytopre-eclampsia:2p13,2p25and9p13.
26,27Notably,theselociaccountforonlyasmallpercentageofcases(otherstudiesfailedtoconfirmtheassociations).
28,29Afourthlocusforpre-eclampsiawassubsequentlyidenti-fiedon10q22.
Maximalallelesharingbetweenpre-eclampticsistersatthislocuswasobservedformaternal-derivedbutnotpaternal-derivedalleles,30indicatingmatrilinealinheritance.
TheSTOX1geneinthe10q22locuscontainsfivedifferentmissensemutations.
STOX1isidenticalinaffectedsisters,co-segregateswiththepre-eclampticphenotypeandisinheritedmatrilineally.
31Arolehasbeenproposedforthegeneproduct(aDNA-bindingprotein)incontrollingpolyploidizationofextravilloustrophoblasts,althoughitsprecisebiologicalfunctionhasnotbeenclarified.
31InalargestudybytheBritishGeneticsofPre-eclampsiaConsortium,657womenaffectedbypre-eclampsiaandtheirfamiliesweregenotypedatsitesof28single-nucleotidepolymorphismsinseveralgenes,includingthoseinvolvedinangiotensinactivity(angiotensinogenandangiotensinIItype1receptor[AT1])andoxida-tivestress(methylenetetrahydrofolatereduc-tase).
32Noneofthegeneticvariantstestedwerefoundtoconferahighriskofdiseasedevelop-ment,indicatingthatalterationsofangiotensinactivityandoxidativestressarenotprimecausesofpre-eclampsia.
DIAGNOSISANDCLINICALFEATURESThecardinalfeaturesofpre-eclampsiaarehypertensionandproteinuria.
Inthepast,hyper-tensionindicativeofpre-eclampsiawasdefinedasanelevationof>30mmHgsystolicpressureor>15mmHgdiastolicpressureabovethepatient'sbaselinebloodpressure.
Thisdefinitionprovedtobeapoorindicatorofoutcome33and,in2000,thecriteriawererefinedbytheNationalHighBloodPressureEducationProgram(NHBPEP)WorkingGroup.
1Sincethen,therehasbeenconsiderableagreementbetweeninternationalworkinggroups.
34Thecriteriadefinehyper-tensionasasystolicbloodpressure≥140mmHgoradiastoliclevel(Korotkoff5)≥90mmHgontwoormoreoccasionsatleast4–6h(butnotmorethan7days)apartafter20weeksofgesta-tioninawomanwithpreviouslynormalbloodpressure.
Nevertheless,theNHBPEPworkinggroupreport1alsostatedthecollectiveopinionthat30mmHgsystolicand15mmHgdiastolicincreases,evenatvalues140mmHg,diastolicbloodpressure>90mmHg1Proteinuria:urinaryproteinexcretion>300mg/day;preservationofpodocytefootprocessesinthepresenceofsubstantialproteinuria137Decreasedplasmavolume:contractedby30–40%comparedwithnormalpregnancy138Edema:interstitialfluidretention;multifactorial138(observedin>50%ofnormalgravidas)Decreasedrenalbloodflow:renalperfusionlessthaninnormalpregnantwomen101Increasedplasmauricacid:secondarytoreduceduricacidrenalclearance139Increasedaminotransferasesandlactatedehydrogenase:hepatocellularnecrosiswithleakageofliverenzymesintomaternalblood140Cerebraledema:duetohypertensionandvascularautoregulatorydysfunction141Thrombocytopenia:plateletcount/=15mmHginassociationwithproteinuriaAmJObstetGynecol183:787–79234BrownMAetal.
(2001)Theclassificationanddiagnosisofthehypertensivedisordersofpregnancy:astatementfromtheInternationalSocietyfortheStudyofHypertensioninPregnancy(ISSHP).
HypertensPregn20:IX–XIV35WaughJJetal.
(2004)Accuracyofurinalysisdipsticktechniquesinpredictingsignificantproteinuriainpregnancy.
ObstetGynecol103:769–77736SibaiBM(2004)Diagnosis,controversies,andmanagementofHELLPsyndrome.
ObstetGynecol103:981–99137YamasmitWetal.
(2004)Randomurinaryprotein-to-creatinineratioforpredictionofsignificantproteinuriainwomenwithpreeclampsia.
JMaternFetalNeonatalMed16:275–27938BrownMAetal.
(2000)Thedetection,investigationandmanagementofhypertensioninpregnancy:executivesummary.
AustNZJObstetGynecol40:133–13839SibaiBM(2002)Chronichypertensioninpregnancy.
ObstetGynecol100:369–37740GilstrapLCIIIandRaminSMonbehalfoftheACOGCommitteeonPracticeBulletin(2002)Diagnosisandmanagementofpreeclampsiaandeclampsia.
IntJObstetGynecol77:67–7541MoranPetal.
(2004)Therenalresponsetopreeclampsia.
SeminNephrol24:588–59542HibbardJUetal.
(2004)Cardiovascularchangesinpreeclampsia.
SeminNephrol24:580–58743HaukkamaaLetal.
(2004)Riskforsubsequentcoronaryarterydiseaseafterpreeclampsia.
AmJCardiol93:805–808NaturePublishingGroup2005REVIEW112NATURECLINICALPRACTICENEPHROLOGYNORISETAL.
DECEMBER2005VOL1NO2www.
nature.
com/clinicalpractice/neph44ZhangJetal.
(2003)SeverematernalmorbidityassociatedwithhypertensivedisordersinpregnancyintheUnitedStates.
HypertensPregn22:203–21245HauthJCetal.
(2000)Pregnancyoutcomesinhealthynulliparouswomenwhosubsequentlydevelopedhypertension.
ObstetGynecol95:24–2846BuchbinderAetal.
(2002)Adverseperinataloutcomesaresignificantlyhigherinseveregestationalhypertensionthaninmildpreeclampsia.
AmJObstetGynecol186:66–7147DuleyL(2003)Pre-eclampsiaandthehypertensivedisordersofpregnancy.
BrMedBull67:161–17648Conde-AgudeloAetal.
(2004)WorldHealthOrganizationsystematicreviewofscreeningtestsforpreeclampsia.
ObstetGynecol104:1367–139149NorthRA(2003)Canwepredictpre-eclampsiaInPreeclampsia,257–275(EdsCritchleyHetal.
)London:RCOGPress50Axt-FliednerR(2004)SecondtrimesteruterinearteryDopplerultrasoundasascreeningtestforadversepregnancyoutcome.
ClinExpObstetGynecol31:9–1151Red-HorseKetal.
(2004)Trophoblastdifferentiationduringembryoimplantationandformationofthematernal–fetalinterface.
JClinInvest114:744–75452LyallF(2005)Primingandremodellingofhumanplacentalbedspiralarteriesduringpregnancy—areview.
Placenta26(SupplA):S31–S3653ZhouYetal.
(1997)Preeclampsiaisassociatedwithfailureofhumancytotrophoblaststomimicavascularadhesionphenotype:OnecauseofdefectiveendovascularinvasioninthissyndromeJClinInvest99:2152–216454PijnenborgRetal.
(1991)Placentalbedspiralarteriesinthehypertensivedisordersofpregnancy.
BrJObstetGynaecol98:648–65555KadyrovMetal.
(2003)Preeclampsiaandmaternalanemiadisplayreducedapoptosisandoppositeinvasivephenotypesofextravilloustrophoblast.
Placenta24:540–54856MoldenhauerJSetal.
(2003)Thefrequencyandseverityofplacentalfindingsinwomenwithpreeclampsiaaregestationalagedependent.
AmJObstetGynecol189:1173–117757TeasdaleF(1985)Histomorphometryofthehumanplacentainmaternalpreeclampsia.
AmJObstetGynecol152:25–3158Moffett-KingA(2002)Naturalkillercellsandpregnancy.
NatRevImmunol2:656–66359ParhamP(2004)NKcellsandtrophoblasts:partnersinpregnancy.
JExpMed200:951–95560HibySEetal.
(2004)CombinationsofmaternalKIRandfetalHLA-Cgenesinfluencetheriskofpreeclampsiaandreproductivesuccess.
JExpMed200:957–96561ZhouYetal.
(1997)Humancytotrophoblastsadoptavascularphenotypeastheydifferentiate.
AstrategyforsuccessfulendovascularinvasionJClinInvest99:2139–215162SharkeyAetal.
(1993)Expressionofvascularendothelialgrowthfactorinhumanplacenta.
JReprodFertil99:609–61563ZhouYetal.
(2002)Vascularendothelialgrowthfactorligandsandreceptorsthatregulatehumancytotrophoblastsurvivalaredysregulatedinseverepreeclampsiaandhemolysis,elevatedliverenzymes,andlowplateletssyndrome.
AmJPathol160:1405–142364CooperJetal.
(1996)VEGFmRNAlevelsinplacentaefrompregnanciescomplicatedbypreeclampsia.
BrJObstetGynaecol103:1191–119665LevineRetal.
(2004)Circulatingangiogenicfactorsandtheriskofpreeclampsia.
NEnglJMed350:672–68366MaynardSetal.
(2003)Excessplacentalsolublefms-liketyrosinekinase1(sFlt1)maycontributetoendothelialdysfunction,hypertension,andproteinuriainpreeclampsia.
JClinInvest111:649–65867HirashimaMetal.
(2003)Trophoblastexpressionoffms-liketyrosinekinase1isnotrequiredfortheestablishmentofthematernal-fetalinterfaceinthemouseplacenta.
ProcNatlAcadSciUSA100:15637–1564268PapapetropoulosAetal.
(1997)Nitricoxideproductioncontributestotheangiogenicpropertiesofvascularendothelialgrowthfactorinhumanendothelialcells.
JClinInvest100:3131–313969MoncadaSandHiggsA(1993)TheL-arginine-nitricoxidepathway.
NEnglJMed329:2002–201270BaylisCetal.
(1998)Recentinsightsintotherolesofnitricoxideandrenin-angiotensininthepathophysiologyofpreeclampticpregnancy.
SeminNephrol18:208–23071ThomsonAJetal.
(1997)Nitricoxidesynthaseactivityandlocalizationdonotchangeinuterusandplacentaduringhumanparturition.
HumReprod12:2546–255272MartinDandConradKP(2000)Expressionofendothelialnitricoxidesynthasebyextravilloustrophoblastcellsinthehumanplacenta.
Placenta21:23–3173EisALetal.
(1995)Immunohistochemicallocalizationofendothelialnitricoxidesynthaseinhumanvillousandextravilloustrophoblastpopulationsandexpressionduringsyncytiotrophoblastformationinvitro.
Placenta16:113–12674OrangeSJetal.
(2003)Placentalendothelialnitricoxidesynthaselocalizationandexpressioninnormalhumanpregnancyandpre-eclampsia.
ClinExpPharmacolPhysiol30:376–38175LyallFetal.
(1999)Humantrophoblastinvasionandspiralarterytransformation.
Theroleofnitricoxide.
AmJPathol154:1105–111476NovaroVetal.
(2001)Regulationofmetalloproteinasesbynitricoxideinhumantrophoblastcellsinculture.
ReprodFertilDev13:411–42077DavisonJMetal.
(2004)Newaspectsinthepathophysiologyofpreeclampsia.
JAmSocNephrol15:2440–244878DunkCetal.
(2000)Angiopoietin-1andangiopoietin-2activatetrophoblastTie-2topromotegrowthandmigrationduringplacentaldevelopment.
AmJPathol156:2185–219979AhmedAetal.
(1997)RoleofVEGFreceptor-1(Flt-1)inmediatingcalcium-dependentnitricoxidereleaseandlimitingDNAsynthesisinhumantrophoblastcells.
LabInvest76:779–79180ChangCCetal.
(2005)InductionofVE-cadherininratplacentaltrophoblastsbyVEGFthroughaNO-dependentpathway.
Placenta26:234–24181NorisMetal.
(1996)Theroleofvasoactivemoleculesofendothelialorigininthepathophysiologyofnormalpregnancyandpregnancy-inducedhypertension.
CurrOpinNephrolHypertens5:347–35282RadiRetal.
(1991)Peroxynitrite-inducedmembranelipidperoxidation:thecytotoxicpotentialofsuperoxideandnitricoxide.
ArchBiochemBiophys288:481–48783ManyAetal.
(2000)Invasivecytotrophoblastsmanifestevidenceofoxidativestressinpreeclampsia.
AmJPathol156:321–33184WangWetal.
(2000)Superoxideproductionandreactiveoxygenspeciessignalingbyendothelialnitric-oxidesynthase.
JBiolChem275:16899–16903NaturePublishingGroup2005REVIEWDECEMBER2005VOL1NO2NORISETAL.
NATURECLINICALPRACTICENEPHROLOGY113www.
nature.
com/clinicalpractice/neph85XiaYetal.
(1996)Nitricoxidesynthasegeneratessuperoxideandnitricoxideinarginine-depletedcellsleadingtoperoxynitrite-mediatedcellularinjury.
ProcNatlAcadSciUSA93:6770–677486Vasquez-VivarJetal.
(1998)Superoxidegenerationbyendothelialnitricoxidesynthase:theinfluenceofcofactors.
ProcNatlAcadSciUSA95:9220–922587XiaYandZweierJL(1997)Superoxideandperoxynitritegenerationfrominduciblenitricoxidesynthaseinmacrophages.
ProcNatlAcadSciUSA94:6954–695888NorisMetal.
(2004)L-argininedepletioninpreeclampsiaorientsnitricoxidesynthasetowardoxidantspecies.
Hypertension43:614–62289LiHetal.
(2001)RegulatoryroleofarginaseIandIIinnitricoxide,polyamine,andprolinesynthasesinendothelialcells.
AmJPhysiol280:E75–E8290LoweD(2000)Nitricoxidedysfunctioninthepathophysiologyofpreeclampsia.
NitricOxide4:441–45891CarlsenSMetal.
(2005)Earlysecond-trimestermaternalhyperandrogenemiaandsubsequentpreeclampsia:aprospectivestudy.
ActaObstetGynecolScand84:117–12192GermainAetal.
(2004)EvidencesupportingabeneficialroleforlongtermL-argininesupplementationinhighriskpregnancies.
Hypertension44:e193MolnarMetal.
(1994)Prolongedblockadeofnitricoxidesynthesisingravidratsproducessustainedhypertension,proteinuria,thrombocytopenia,andintrauterinegrowthretardation.
AmJObstetGynecol170:1458–146694TanirHMetal.
(2005)Effectofquercetineandglutathioneonthelevelofsuperoxidedismutase,catalase,malonyldialdehyde,bloodpressureandneonataloutcomeinaratmodelofpre-eclampsiainducedbyNG-nitro-L-arginine-methylester.
EurJObstetGynecolReprodBiol118:190–19595CaniggiaIandWinterJL(2002)Hypoxiainduciblefactor-1:oxygenregulationoftrophoblastdifferentiationinnormalandpre-eclampticpregnancies—Areview.
Placenta23(SupplA):S47–S5796RajakumarAetal.
(2004)Evidenceofthefunctionalactivityofhypoxia-inducibletranscriptionfactorsoverexpressedinpreeclampticplacentae.
Placenta25:763–76997CaniggiaIetal.
(2000)Hypoxia-induciblefactor-1mediatesbiologicaleffectsofoxygeninhumantrophoblastdifferentiationthroughTGFβ3.
JClinInvest105:577–58798CaniggiaIetal.
(1999)InhibitionofTGFβ3restorestheinvasivecapabilityofextravilloustrophoblastinpreeclampticpregnancies.
JClinInvest103:1641–165099HungT-Hetal.
(2002)Hypoxia-reoxygenation.
Apotentinducerofapoptoticchangesinthehumanplacentaandpossibleetiologicalfactorinpreeclampsia.
CircRes90:1274–1281100ParksDetal.
(1988)Conversionofxanthinedehydrogenasetooxidaseinischemicratintestine:areevaluation.
AmJPhysiol254:G768–G774101McLaughlinMKandRobertsJM(1999)Hemodynamicchangesinpregnancy.
InHypertensiveDisordersinPregnancy,92–95(EdsLindheimerMDetal.
)Stamford:Appleton&Lange102ShahD(2005)Roleoftherenin–angiotensinsysteminthepathogenesisofpreeclampsia.
AmJRenalPhysiol288:F614–F625103BowyerLetal.
(2003)Forearmbloodflowinpre-eclampsia.
BJOG110:383–391104ElsheikhAetal.
(2001)Therenin-aldosteronesystemduringnormalandhypertensivepregnancy.
ArchGynecolObstet264:182–185105WalshS(2004)Eicosanoidsinpreeclampsia.
ProstaglandinsLeukotEssentFattyAcids70:223–232106SeligmanSPetal.
(1994)Theroleofnitricoxideinthepathogenesisofpreeclampsia.
AmJObstetGynecol171:944–948107GarmendiaJVetal.
(1997)Nitricoxideindifferenttypesofhypertensionduringpregnancy.
ClinSci93:413–421108FicklingSAetal.
(1993)Plasmaconcentrationsofendogenousinhibitorofnitricoxidesynthesisinnormalpregnancyandpre-eclampsia.
Lancet34:242–243109Lopez-JaramilloPetal.
(1996)Cyclicguanosidine3,5monophosphateconcentrationsinpre-eclampsia:effectsofhydralazine.
BrJObstetGynaecol103:33–38110PridjianGandPuschettJB(2002)Preeclampsia.
Part1:Clinicalandpathophysiologicconsiderations.
ObstetGynecolSurv57:598–618111BuhimschiCSetal.
(2005)Urinaryangiogenicfactorsclusterhypertensivedisordersandidentifywomenwithseverepreeclampsia.
AmJObstetGynecol192:734–741112StepanHetal.
(2004)Solublefms-liketyrosinekinase1.
NEnglJMed351:2241–2242113WolfMetal.
(2005)CirculatinglevelsoftheantiangiogenicmarkersFLT-1areincreasedinfirstversussecondpregnancies.
AmJObstetGynecol193:16–22114LuttunAandCarmelietP(2003)SolubleVEGFreceptorFlt1:theelusivepreeclampsiafactordiscoveredJClinInvest111:600–602115LiHetal.
(2005)Hypoxia-inducedincreaseinsolubleFlt-1productioncorrelateswithenhancedoxidativestressintrophoblastcellsfromthehumanplacenta.
Placenta26:210–217116LivingstonJCetal.
(2000)Reductionsofvascularendothelialgrowthfactorandplacentalgrowthfactorconcentrationsinseverepreeclampsia.
AmJObstetGynecol183:1554–1557117LevineRJetal.
(2005)Urinaryplacentalgrowthfactorandriskofpreeclampsia.
JAMA293:77–85118MasudaYetal.
(2001)Vascularendothelialgrowthfactorenhancesglomerularcapillaryrepairandacceleratesresolutionofexperimentallyinducedglomerulonephritis.
AmJPathol159:599–608119SugimotoHetal.
(2003)Neutralizationofcirculatingvascularendothelialgrowthfactor(VEGF)byanti-VEGFantibodiesandsolubleVEGFreceptor1(sFlt-1)inducesproteinuria.
JBiolChem278:12605–12608120YangJetal.
(2003)Arandomizedtrialofbevacizumab,ananti-vascularendothelialgrowthfactorantibody,formetastaticrenalcancer.
NEnglJMed349:427–434121EreminaVetal.
(2003)Glomerular-specificalterationsofVEGF-Aexpressionleadtodistinctcongenitalandacquiredrenaldiseases.
JClinInvest111:707–716122BoydPetal.
(1987)Pre-eclampsiaandtrisomy13:apossibleassociation.
Lancet2:425–427123BdolahYetal.
(2005)Trisomy13andpreeclampsia:anoldlinkwithanewexplanation.
JSocGynecolInvest12(Suppl2):S196A124AbdAllaSetal.
(2001)IncreasedAT1receptorheterodimersinpreeclampsiamediateenhancedangiotensinIIresponsiveness.
NatMed7:1003–1009125DechendRetal.
(2000)AT(1)receptoragonisticantibodiesfrompreeclampticpatientscausevascularcellstoexpresstissuefactor.
Circulation101:2382–2387126BobstSMetal.
(2005)Maternalautoantibodiesfrompreeclampticpatientsactivateangiotensinreceptorsonhumanmesangialcellsandinduceinterleukin-6andplasminogenactivatorinhibitor-1secretion.
AmJHypertens18:330–336NaturePublishingGroup2005REVIEW114NATURECLINICALPRACTICENEPHROLOGYNORISETAL.
DECEMBER2005VOL1NO2www.
nature.
com/clinicalpractice/neph127XiaYetal.
(2003)Maternalautoantibodiesfrompreeclampticpatientsactivateangiotensinreceptorsonhumantrophoblastcells.
JSocGynecolInvestig10:82–93128HubelCetal.
(1989)Lipidperoxidationinpregnancy:Newperspectivesonpreeclampsia.
AmJObstetGynecol161:1025–1034129CosentinoFetal.
(2003)Highglucosecausesupregulationofcyclooxygenase-2andallprostanoidprofileinhumanendothelialcells:roleofproteinkinaseCandreactiveoxygenspecies.
Circulation107:1017–1023130ChappellLetal.
(1999)Effectofantioxidantsontheoccurrenceofpre-eclampsiainwomenatincreasedrisk:arandomizedtrial.
Lancet354:810–816131FacchinettiFetal.
(1999)L-Arginineinfusionreducesbloodpressureinpreeclampticwomenthroughnitricoxiderelease.
JSocGynecolInvest6:202–207132RytlewskiKetal.
(2005)EffectsofprolongedoralsupplementationwithL-arginineonbloodpressureandnitricoxidesynthesisinpreeclampsia.
EurJClinInvest35:32–37133ChappellLetal.
(2002)VitaminCandEsupplementationinwomenatriskofpreeclampsiaisassociatedwithchangesinindicesofoxidativestressandplacentalfunction.
AmJObstetGynecol187:777–784134RobertsJMandSpeerP(2004)Antioxidanttherapytopreventpreeclampsia.
SeminNephrol24:557–564135FraserWDetal.
(2005)ThevitaminEdebate:implicationsforongoingtrialsofpre-eclampsiaprevention.
BJOG112:684–688136SibaiBetal.
(2005)Pre-eclampsia.
Lancet365:785–799137MautnerWetal.
(1962)Preeclampticnephropathy.
Anelectronmicroscopicstudy.
LabInvest11:518–530138GalleryEandLindheimerM(1999)Pathologyandpathophysiologyofpreeclampsia:Alterationsinvolumehomeostasis.
InChesley'sHypertensiveDisordersinPregnancy,327–347(EdsLindheimerMetal.
)Stamford:Appleton&Lange139HayashiT(1956)Uricacidandendogenouscreatinineclearancestudiesinnormalpregnancyandtoxemiasofpregnancy.
AmJObstetGynecol71:859–870140ZissinRetal.
(1999)HepaticinfarctioninpreeclampsiaaspartoftheHELLPsyndrome:CTappearance.
AbdomImaging24:594–596141PortJandBeauchampNJ(1998)Reversibleintracerebralpathologicentitiesmediatedbyvascularautoregulatorydysfunction.
Radiographics18:353–367142SalehAetal.
(1992)Markersforendothelialinjury,clottingandplateletactivationinpreeclampsia.
ArchGynecolObstet251:105–110143StubbsTetal.
(1986)Evidenceofacceleratedplateletproductionandconsumptioninnonthrombocytopenicpreeclampsia.
AmJObstetGynecol155:263–265144LindheimerMD(2005)Unravelingthemysteriesofpreeclampsia.
AmJObstetGynecol193:3–4AcknowledgmentsWeareindebtedtoProfessorFranklinHEpstein(SeniorPhysician,RenalDivision,DepartmentofMedicine,BethIsraelDeaconessMedicalCenter,Boston)andWilliamApplebaum(ProfessorofMedicine,HarvardMedicalSchool,Boston)fortheircriticalreadingofthemanuscriptandinsightfuldiscussion.
WealsothankDrPrudenceHill(DepartmentofAnatomicalPathology,StVincent'sHospital,Melbourne)forhercriticalreading.
CompetinginterestsTheauthorsdeclaredtheyhavenocompetinginterests.
NaturePublishingGroup2005
- producthaole008.com相关文档
- Fillerhaole008.com
- longhaole008.com
- IEChaole008.com
- Zthhaole008.com
- STARThaole008.com
- lbfhaole008.com
Friendhosting四五折促销,VPS半年付7.5欧元起
Friendhosting发布了针对“系统管理日”(每年7月的最后一个星期五)的优惠活动，针对VPS主机提供55%的优惠(相当于四五折)，支持1-6个月付款使用，首付折扣非永久，优惠后最低套餐首半年7.18欧元起。这是一家保加利亚主机商，成立于2009年4月，商家提供VDS和独立服务器租用等，数据中心目前可选美国洛杉矶、保加利亚、乌克兰、荷兰、拉脱维亚、捷克和波兰等8个地区机房。下面以最低套餐为例...
腾讯云2核4GB内存8M带宽 年74元
一般大厂都是通过首年才有可以享受爆款活动，然后吸引我们注册他们商家达到持续续费和购买的目的。一般只有大厂才能有这样的魄力和能力首年亏本，但是对于一般的公司和个人厂家确实难过，这几年确实看到不少的同类商家难以生存。这里我们可以看到有对应的套餐方案。不过这两个套餐都是100%CPU独享的，不是有某云商家限制CPU的。但是轻量服务器有个不好的就是带宽是较大且流量是限制的额，分别是1GB和1.2TB月流量...
青云互联19元/月，美国洛杉矶CN2GIA/香港安畅CN2云服务器低至;日本云主机
青云互联怎么样?青云互联美国洛杉矶cn2GIA云服务器低至19元/月起;香港安畅cn2云服务器低至19元/月起;日本cn2云主机低至35元/月起!青云互联是一家成立于2020年的主机服务商,致力于为用户提供高性价比稳定快速的主机托管服务。青云互联本站之前已经更新过很多相关文章介绍了，青云互联的机房有香港和洛杉矶，都有CN2 GIA线路、洛杉矶带高防，商家承诺试用7天，打死全额退款点击进入：青云互联...
haole008.com为你推荐
-
敬汉卿姓名被抢注身份证号码被别人抢注了12306帐号怎么办特朗普取消访问丹麦特朗普专机抵达日本安保警力情形如何？对对塔为什么不能玩天天擂台？（对对塔）网红名字被抢注想用的微博名被人抢注了 而且是个死号 没发博没粉丝 该怎么办地图应用什么地图导航最好用最准确陈嘉垣陈嘉桓是谁?m.2828dy.comwww.dy6868.com这个电影网怎么样?www.toutoulu.comWWW【toutoulu】cOM怎么搜不到了？到哪里能看到toutoulu视频？梦遗姐昨晚和姐姐和她朋友一起吃晚饭，我们都喝了酒，我迷糊着回到家的，早上我回想起我好像发生关系射过，会不会是我姐姐，如果是这样我怎么办汴京清谈汴京还被称为什么？