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
一键去除宝塔面板各种计算题与延时等待
现在宝塔面板真的是越来越过分了，删除文件、删除数据库、删除站点等操作都需要做计算题！我今天升级到7.7版本，发现删除数据库竟然还加了几秒的延时等待，也无法跳过！宝塔的老板该不会是小学数学老师吧，那么喜欢让我们做计算题！因此我写了个js用于去除各种计算题以及延时等待，同时还去除了软件列表页面的bt企业版广告。只需要执行以下命令即可一键完成！复制以下命令在SSH界面执行：Layout_file="/w...
特网云57元，香港云主机 1核 1G 10M宽带1G(防御)
特网云官網特网云服务器在硬件级别上实现云主机之间的完全隔离；采用高端服务器进行部署，同时采用集中的管理与监控，确保业务稳定可靠，搭建纯SSD架构的高性能企业级云服务器，同时采用Intel Haswell CPU、高频DDR4内存、高速Sas3 SSD闪存作为底层硬件配置，分钟级响应速度，特网云采用自带硬防节点，部分节点享免费20G防御，可实现300G防御峰值，有效防御DDoS、CC等恶意攻击，保障...
麻花云-香港CN2云服务器，安徽BGP线路，安徽移动大带宽！全系6折！
一、麻花云官网点击直达麻花云官方网站二、活动方案优惠码：专属优惠码：F1B07B 享受85折优惠。点击访问活动链接最新活动 :五一狂欢 惠战到底 香港云主机 1.9折起香港特价体验云主机CN2 云服务器最新上线KVM架构，，默认40G SSD，+10G自带一个IPv4，免费10Gbps防御，CPU内存带宽价格购买1核1G1M19元首月链接2核2G 2M92元/3个月链接2核4G3M112元/3个月...
haole008.com为你推荐
-
咏春大师被ko大师：咏春是不会败的 教练：能不偷袭吗，咏春拳教练阿丽克丝·布莱肯瑞吉阿丽克斯布莱肯瑞吉演的美国恐怖故事哪两集比肩工场比肩夺财，行官杀制比是什么意思？罗伦佐娜罗拉芳娜 （西班牙小姐）谁可以简单的介绍以下罗伦佐娜维洛娜毛周角化修复液治疗毛周角化有用吗？谁用过？能告诉我吗？月神谭给点人妖。变身类得小说。百花百游迎得春来非自足，百花千卉共芬芳什么意思seo优化工具SEO优化要用到什么软件？www.kk4kk.com猪猪影院www.mlzz.com 最新电影收费吗？www.7788dy.comwww.tom365.com这个免费的电影网站有毒吗?