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
项目摘要/摘要:在人类妊娠早期,胎盘绒毛外滋养细胞(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),从而导致
孕产妇和新生儿发病率/死亡率。相反,过度的UAR,如植入性胎盘,会损害
分娩后的血管调节。尽管UAR对成功妊娠很重要,但人们对此知之甚少
UAR法规。使用狒狒作为非人类灵长类动物的翻译模型,我们已经证明了
将雌二醇(E_2)的峰值从妊娠中期提前到妊娠早期抑制了UAR和EVT
血管内皮生长因子(VEGF)的表达。因此,我们建议:(A)香港的雌二醇水平偏低。
早孕促进EVT、血管内皮生长因子表达和UAR及(B)中孕期E2水平升高
通过抑制血管内皮生长因子抑制UAR。因为抑制UAR的E2仅仅与一种
血管内皮生长因子的表达降低,目前尚不清楚血管内皮生长因子是否介导了这一过程。因此,在AIMS中
我们建议使用对比增强超声(CEU)/微泡(MB)靶向传递血管内皮生长因子
雌激素2处理的狒狒胎盘基板基因和抑制血管内皮生长因子的sFlt-1基因
未经处理的狒狒的生物利用度,以检验关于血管内皮生长因子:(A)介导E2诱导的假说
在正常妊娠期间抑制UAR和(B)促进UAR。UAR的缺陷损害胎盘
功能,导致胎盘sFlt-1表达增加/VEGF可获得性下降,从而
母体血管功能紊乱。因此,在AIM 1C中,血流动力学将是
确定用于测试E2诱导sFlt-1增加/VEGF减少的假设
生物利用度导致母体血管功能障碍。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态的方式发生,在AIM 1D UAR和母体中
将在有男性和女性胎儿的怀孕中测定血管功能,以检验这一假设
胎儿性别影响后一种过程。虽然E2通常会上调血管内皮生长因子,但雌二醇会降低EVT血管内皮生长因子
表情。雌激素对血管内皮生长因子表达的不同作用可能反映了雌激素受体的表达/作用
(呃)α对ERβ。因此,在目标1E中,我们将培养狒狒胚胎成纤维细胞,以检验ERβ介导的假设
E2诱导抑制EVT血管内皮生长因子的表达、迁移和侵袭。拟议的研究具有很高的
意义重大,因为它集中在UAR的调节上,当缺陷时,UAR是异常妊娠的基础。这个
实验范式和通过CEU/MB靶向传递VEGF/sFlt-1基因是新的前沿
确定血管内皮生长因子在正常和异常UAR中的作用的方法
对人类的翻译应用。阐明血管内皮生长因子在UAR中的作用将具有重大的科学意义
为血管内皮生长因子靶向治疗人类妊娠疾病提供依据。
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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