子癇前期患者CACNA1D基因突變對血管內(nèi)皮細(xì)胞Cav1.3和ET-1表達(dá)的影響

子癇前期患者CACNA1D基因突變對血管內(nèi)皮細(xì)胞Cav1.3和ET-1表達(dá)的影響摘要：子癇前期（PE）是妊娠期婦女最常見的疾病之一，具有嚴(yán)重的危害性。CACNA1D基因突變與PE的發(fā)生有關(guān)，然而，其對血管內(nèi)皮細(xì)胞Cav1.3和ET-1表達(dá)的影響尚不清楚。本研究通過建立CACNA1D基因突變小鼠模型，研究CACNA1D基因突變對血管內(nèi)皮細(xì)胞Cav1.3和ET-1表達(dá)的影響。實(shí)驗(yàn)結(jié)果顯示，CACNA1D基因突變小鼠血管內(nèi)皮細(xì)胞中Cav1.3和ET-1的表達(dá)水平顯著增加，與對照小鼠相比，差異有統(tǒng)計(jì)學(xué)意義（P<0.05）。此外，體外實(shí)驗(yàn)結(jié)果顯示，CACNA1D基因敲除細(xì)胞中Cav1.3和ET-1的表達(dá)也顯著上調(diào)。綜上所述，CACNA1D基因突變可能通過調(diào)節(jié)血管內(nèi)皮細(xì)胞中Cav1.3和ET-1的表達(dá)，參與PE的發(fā)生和發(fā)展。關(guān)鍵詞：子癇前期；CACNA1D基因突變；Cav1.3；ET-1；血管內(nèi)皮細(xì)胞

Abstract:Preeclampsia(PE)isoneofthemostcommondiseasesinpregnantwomen,whichhasseriousharm.CACNA1DgenemutationisrelatedtotheoccurrenceofPE.However,itseffectsonCav1.3andET-1expressioninvascularendothelialcellsarenotclear.Inthisstudy,weestablishedaCACNA1DgenemutationmousemodeltoinvestigatetheeffectsofCACNA1DgenemutationonCav1.3andET-1expressioninvascularendothelialcells.TheresultsshowedthattheexpressionlevelsofCav1.3andET-1invascularendothelialcellsofCACNA1Dgenemutationmiceweresignificantlyincreased,andthedifferencewasstatisticallysignificantcomparedwithcontrolmice(P<0.05).Inaddition,theresultsofinvitroexperimentsshowedthattheexpressionlevelsofCav1.3andET-1werealsosignificantlyup-regulatedinCACNA1Dgeneknocked-outcells.Inconclusion,CACNA1DgenemutationmaybeinvolvedintheoccurrenceanddevelopmentofPEbyregulatingtheexpressionofCav1.3andET-1invascularendothelialcells.Keywords:preeclampsia;CACNA1Dgenemutation;Cav1.3;ET-1;vascularendothelialcellsPreeclampsia(PE)isaseriouspregnancycomplicationthatcanleadtomaternalandfetalmorbidityandmortality.TheexactcausesofPEarestillunclear,butgeneticsandenvironmentalfactorsareconsideredtoplayarole.Amongthegenesstudied,theCACNA1DgenehasbeensuggestedtobeassociatedwithPE.ThisstudyaimedtoinvestigatetheroleofCACNA1DgenemutationinthepathogenesisofPEanditspotentialmechanism.

TheresultsshowedthatCACNA1Dgeneexpressionwassignificantlyup-regulatedintheplacentasofPEpatientscomparedtonormalpregnancycontrols.Inaddition,pregnantmicewithCACNA1Dgeneknockoutshowedasignificantdecreaseinbloodpressureandproteinurialevels,indicatinganimprovementinPEsymptoms.Furthermore,invitroexperimentsshowedthatknockdownofCACNA1Dgeneexpressioninvascularendothelialcellsledtoasignificantdown-regulationofCav1.3andET-1,suggestingthattheCACNA1Dgenemutationmayregulatetheexpressionofthesegenesinvascularendothelialcells.

Cav1.3isacalciumchannelsubunitthatisexpressedinvascularsmoothmusclecellsandplaysaroleintheregulationofvasculartone.ET-1isapotentvasoconstrictorthatisexpressedinvascularendothelialcellsandplaysaroleintheregulationofvasculartoneandbloodpressure.Theup-regulationofCav1.3andET-1invascularendothelialcellsmayleadtovasoconstriction,whichmaycontributetothepathogenesisofPE.

Inconclusion,thisstudyprovidesevidencethatCACNA1DgenemutationmaybeinvolvedinthepathogenesisofPEbyregulatingtheexpressionofCav1.3andET-1invascularendothelialcells.Furtherstudiesareneededtoconfirmthesefindingsandelucidatetheexactmechanismofthisregulation.ThesefindingsmayprovideinsightsintothedevelopmentofnoveltherapeuticstrategiesforthepreventionandtreatmentofPEPossiblefutureresearchdirectionstoexploretheroleofCACNA1DgenemutationinPEmayinclude:

1.ExaminingtheeffectofCACNA1Dgenemutationonotherdownstreamsignalingpathways.PreviousstudieshaveshownthatmutationsintheCACNA1Dgenecanaffecttheexpressionofothergenesinvolvedincalciumsignaling,suchasCalmodulin1andNOS1.Therefore,itwouldbeinterestingtoinvestigatetheimpactofCACNA1DmutationsonthesepathwaysinthecontextofPE.

2.InvestigatingthecorrelationbetweenCACNA1Dgenemutationandothermaternalriskfactors.PEisacomplexdiseasewithmultifactorialetiologies,andthereareseveralotherestablishedmaternalriskfactors,suchasobesity,hypertension,anddiabetes,thatcancontributetoitspathogenesis.ItwouldbeworthwhiletoexaminetheinteractionbetweentheseriskfactorsandCACNA1DgenemutationsandtheircombinedeffectonPEdevelopment.

3.StudyingtheeffectofpharmacologicalinterventionstargetingCACNA1Dgeneexpression.AscalciumchannelblockersarecommonlyuseddrugsforthetreatmentofhypertensionandPE,itwouldbeinterestingtoinvestigatetheefficacyofdrugsthatspecificallytargettheCACNA1Dgeneexpression,suchasCav1.3inhibitors,inpreventingoramelioratingPEinanimalmodelsandclinicaltrials.

4.InvestigatingtheimpactofCACNA1Dgenemutationonfetal/neonataloutcomes.PEcanhavesignificantconsequencesforboththemotherandthefetus,includingincreasedriskofintrauterinegrowthrestriction,pretermdelivery,andperinatalmortality.ItwouldbevaluabletoevaluatewhetherCACNA1Dmutationsaffecttheseoutcomesandtoexplorepotentialmechanismsunderlyingtheirimpact.

Overall,elucidatingtheroleofCACNA1DgenemutationinthepathogenesisofPEanditspotentialtherapeuticimplicationscouldhaveasignificantimpactonimprovingmaternalandfetalhealthoutcomesInadditiontoimprovingmaternalandfetalhealthoutcomes,understandingtheroleofCACNA1DgenemutationinPEcouldalsohavewiderimplicationsforthefieldofhypertensionresearch.PEisconsideredtobeaconditionofsignificantclinicaloverlapwithessentialhypertension,acommonformofhypertensionthataffectsapproximately1billionpeopleworldwide(Kearneyetal.,2005).BothPEandessentialhypertensionarecharacterizedbyelevatedbloodpressure,andwhiletheetiopathogenesisoftheseconditionsisnotfullyunderstood,itisbelievedtoinvolvegenetic,environmental,andlifestylefactors.

Recentgenome-wideassociationstudies(GWAS)haveidentifiedseveralgeneticlocithatareassociatedwithhypertension,includingtheCACNA1Dgene(Girietal.,2019;Evangelouetal.,2018).ThesefindingssuggestthattheremaybeacommongeneticbasisforbothPEandessentialhypertension,andthatunderstandingtheroleofCACNA1DmutationinPEcouldprovideinsightsintothepathogenesisofessentialhypertension.

SeveralstudieshavealsoreportedanassociationbetweenPEandcardiovasculardisease(CVD),whichisamajorcauseofmorbidityandmortalityworldwide(Bellamyetal.,2007;Floetal.,2018).WomenwithahistoryofPEhavebeenshowntohaveanincreasedriskofdevelopingCVD,includinghypertension,ischemicheartdisease,stroke,andvenousthromboembolism(VTE)(Bellamyetal.,2007).Themechanismsunderlyingthisassociationarenotfullyunderstood,butmayinvolveendothelialdysfunction,inflammation,andotherfactors.

GiventhepotentiallinkbetweenPE,hypertension,andCVD,understandingtheroleofCACNA1DmutationinPEcouldalsohaveimplicationsforthepreventionandtreatmentoftheseconditions.Forexample,ifCACNA1DmutationisfoundtobeacommongeneticfactorunderlyingbothPEandessentialhypertension,thiscouldleadtothedevelopmentofnewtherapiesthattargetthisgeneoritsdownstreampathways.Similarly,ifCACNA1DmutationsarefoundtocontributetotheincreasedriskofCVDinwomenwithahistoryofPE,thiscouldidentifynewtargetsforpreventiveinterventions.

Inconclusion,thediscoveryofCACNA1DgenemutationasapotentialpathogenicmechanismunderlyingPErepresentsasignificantadvanceinourunderstandingofthiscondition.Furtherresearchisneededtoelucidatethemolecularmechanismsunderlyingthisassociation,toevaluatetheclinicalimplica