Regulation of Uterine Spiral Artery Remodeling During Primate Pregnancy
Regulation of Uterine Spiral Artery Remodeling During Primate Pregnancy
批准号:
9365496
负责人:
Eugene D. Albrecht
金额:
$64.02万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-09-08 至 2022-06-30
关键词:
AreaArteriesBasal PlateBindingBiological AvailabilityBiologyBlood VesselsBlood flowCellsDefectDiseaseEstradiolEstrogen Receptor alphaEstrogen Receptor betaEstrogen ReceptorsEstrogensEtiologyFemaleFetal DevelopmentFetal Growth RetardationFetusFirst Pregnancy TrimesterFunctional disorderGenderGene DeliveryGene TargetingGenesHumanImpairmentInvadedLeadMediatingMicrobubblesModelingOvarianPapioPerinatalPhysiologicalPlacentaPlacenta AccretaPlacenta DiseasesPre-EclampsiaPregnancyPregnancy RatePremature BirthPrimatesProcessRegulationResearchResistanceRoleScientific Advances and AccomplishmentsSecond Pregnancy TrimesterSerumSmooth MuscleSolidSpiral Artery of the EndometriumSyndromeTechnologyTestingTherapeuticTissuesUltrasonographyVEGFA geneVascular DiseasesVascular Endothelial CellVascular Endothelial Growth Factor BVascular Endothelial Growth FactorsVasomotorbrachial arterycontrast enhancedfetalhuman diseasein vivoindexinginnovationmalematernal morbiditymigrationmortalityneonatal morbiditynonhuman primatenovelperipheral blood vesselpregnancy disorderprematurereceptortargeted deliverytrophoblast
中文摘要
项目总结/摘要:在人类妊娠早期,胎盘绒毛外滋养层细胞(EVT)
重塑子宫螺旋动脉(UAR)以促进子宫-胎盘血流和胎儿发育。
UAR受损是妊娠障碍的基础,例如胎儿生长受限和先兆子痫(PE),其导致
产妇和新生儿发病率/死亡率。相反,过多的UAR,如胎盘植入,
分娩后的血管调节。尽管UAR对成功怀孕的重要性,但人们对UAR的了解很少。
UAR法规。使用狒狒作为非人灵长类动物的翻译模型,我们已经表明,
将雌二醇(E2)高峰从孕中期提前到孕早期抑制UAR和EVT
血管内皮生长因子(VEGF)的表达。因此,我们建议:(a)低水平的E2,
前三个月促进EVT VEGF表达和UAR,和(B)在后三个月E2增加
通过抑制EVT VEGF抑制UAR。因为E2抑制UAR仅仅与
尽管EVT VEGF表达减少,但VEGF是否介导该过程尚不清楚。因此,在目标
在图1A、B中,我们提出使用造影剂增强超声(CEU)/微泡(MB)靶向递送VEGF
E2处理狒狒胎盘基板的sFlt-1基因和抑制VEGF的sFlt-1基因
生物利用度测试的假设,VEGF:(a)介导E2诱导的
抑制UAR和(B)在正常妊娠期间促进UAR。UAR缺陷损害胎盘
功能,导致胎盘sFlt-1表达增加/VEGF可用性下降,
破坏母体全身血管功能。因此,在目标1C中,血流动力学将是
在狒狒中测定,以检验E2诱导的sFlt-1增加/VEGF减少
生物利用度导致母体全身血管功能障碍。因为胎盘功能障碍和血管
妊娠障碍中的缺陷以胎儿性别二型的方式发生,在Aim 1D UAR和母体
将在有男性和女性胎儿的妊娠中测定血管功能,以检验以下假设:
胎儿性别影响后面的过程。虽然E2通常上调VEGF,但E2降低EVT VEGF
表情E2对VEGF表达的不同作用可能反映了雌激素受体的表达/作用
(ER)α与ERβ。因此,在目的1 E中,我们将培养狒狒EVT以检验ERβ介导
E2诱导的EVT VEGF表达、迁移和侵袭的抑制。这项研究建议高度
重要的是,它侧重于UAR的调节,当有缺陷时,UAR是异常妊娠的基础。的
实验范例和通过CEU/MB靶向递送VEGF/sFlt-1基因是新的前沿
这些方法将建立VEGF对具有大量UAR的灵长类动物中正常和异常UAR的作用,
翻译应用于人类。阐明VEGF在UAR中的作用将是一个重要的科学研究方向。
为VEGF靶向在人类妊娠疾病中的治疗应用提供了基础。
英文摘要
PROJECT SUMMARY/ABSTRACT: During early human pregnancy, placental extravillous trophoblasts (EVT)
remodel the uterine spiral arteries (UAR) to promote utero-placental blood flow and fetal development.
Impaired UAR underlies pregnancy disorders, e.g. fetal growth restriction and preeclampsia (PE), which result
in maternal and neonatal morbidity/mortality. Conversely, excessive UAR, as in placenta accreta, impairs
vasoregulation after delivery. Despite the importance of UAR to successful pregnancy little is known about
UAR regulation. Using the baboon as a nonhuman primate translational model, we have shown that
advancing the surge in estradiol (E2) from the second to the first trimester suppressed UAR and EVT
expression of vascular endothelial growth factor (VEGF). Therefore, we propose that: (a) the low level of E2 in
the first trimester promotes EVT VEGF expression and UAR and (b) the increase in E2 in the second trimester
suppresses UAR by inhibiting EVT VEGF. Because E2 suppression of UAR was simply associated with a
decrease in EVT VEGF expression, it is not known whether VEGF mediates this process. Therefore, in Aims
1A,B we propose to use contrast enhanced ultrasound (CEU)/microbubble (MB) targeting to deliver the VEGF
gene to the placental basal plate of E2-treated baboons and the sFlt-1 gene which suppresses VEGF
bioavailability to untreated baboons to test the hypotheses that VEGF: (a) mediates the E2-induced
suppression of UAR and (b) promotes UAR during normal pregnancy. A defect in UAR impairs placental
function, leading to an increase in placental sFlt-1 expression/decline in VEGF availability and consequently
disruption of maternal systemic vascular function. Therefore, in Aim 1C, blood flow dynamics will be
determined in baboons to test the hypothesis that the E2-induced increase in sFlt-1/decrease in VEGF
bioavailability results in maternal systemic vascular dysfunction. Because placental dysfunction and vascular
defects in pregnancy disorders occur in a fetal sexual dimorphic manner, in Aim 1D UAR and maternal
vascular function will be determined in pregnancies with male and female fetuses to test the hypothesis that
fetal gender impacts the latter processes. Although E2 typically upregulates VEGF, E2 decreased EVT VEGF
expression. The divergent roles of E2 on VEGF expression may reflect expression/action of estrogen receptor
(ER)α versus ERβ. Therefore, in Aim 1E we will culture baboon EVT to test the hypothesis that ERβ mediates
E2-induced suppression of EVT VEGF expression, migration and invasion. The proposed study is highly
significant as it focuses on the regulation of UAR which when defective underpins abnormal pregnancy. The
experimental paradigm and targeted delivery of VEGF/sFlt-1 genes via CEU/MB are novel cutting-edge
approaches that will establish the role of VEGF on normal and abnormal UAR in a primate with substantial
translational application to humans. Elucidating the role of VEGF on UAR will represent a major scientific
advance and provide a basis for therapeutic application of VEGF targeting in disorders of human pregnancy.
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