Regulation of Uterine Spiral Artery Remodeling During Primate Pregnancy

灵长类动物妊娠期间子宫螺旋动脉重塑的调节

• 批准号: 10189673
• 负责人: Eugene D. Albrecht
• 金额: $ 61.56万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-08 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10189673
• 关键词: Area; Arteries; Basal Plate; Binding; Biological Availability; Biology; Blood Vessels; Blood flow; Cells; Defect; Disease; Endothelial Growth Factors Receptor; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Estrogens; Etiology; Female; Fetal Development; Fetal Growth Retardation; Fetus; First Pregnancy Trimester; Functional disorder; Gender; Gene Delivery; Gene Targeting; Genes; Growth Factor Gene; Human; Impairment; Invaded; Lead; Mediating; Microbubbles; Modeling; Ovarian; Papio; Perinatal; Physiological; Placenta; Placenta Accreta; Placenta Diseases; Pre-Eclampsia; Pregnancy; Pregnancy Rate; Premature Birth; Primates; Process; Regulation; Research; Resistance; Role; Scientific Advances and Accomplishments; Second Pregnancy Trimester; Serum; Smooth Muscle; Solid; Spiral Artery of the Endometrium; Syndrome; Technology; Testing; Therapeutic; Tissues; Ultrasonography; Uterus; VEGFA gene; Vascular Diseases; Vascular Endothelial Cell; Vascular Endothelial Growth Factor B; Vascular Endothelial Growth Factors; Vascular Endothelium; Vasomotor; brachial artery; contrast enhanced; fetal; human disease; in vivo; indexing; innovation; male; maternal morbidity; migration; mortality; neonatal morbidity; nonhuman primate; novel; peripheral blood vessel; pregnancy disorder; premature; receptor; sexual dimorphism; targeted delivery; translational model; trophoblast

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.

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。 受损的 UAR 是妊娠疾病的基础，例如妊娠期疾病。胎儿生长受限和先兆子痫 (PE)，这会导致 孕产妇和新生儿发病率/死亡率。相反，过多的 UAR（如植入性胎盘）会损害 产后血管调节。尽管 UAR 对于成功怀孕的重要性却知之甚少 UAR 监管。使用狒狒作为非人类灵长类动物翻译模型，我们已经证明 将雌二醇 (E2) 的激增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) E2 水平较低 妊娠早期促进 EVT VEGF 表达和 UAR 以及 (b) 妊娠中期 E2 的增加 通过抑制 EVT VEGF 来抑制 UAR。因为 UAR 的 E2 抑制仅与 EVT VEGF 表达减少，但尚不清楚 VEGF 是否介导此过程。因此，在目标 1A,B 我们建议使用对比增强超声 (CEU)/微泡 (MB) 靶向来递送 VEGF E2 处理狒狒胎盘基底板的基因和抑制 VEGF 的 sFlt-1 基因 对未经治疗的狒狒进行生物利用度测试，以测试 VEGF 的假设：(a) 介导 E2 诱导的 抑制 UAR 和 (b) 在正常妊娠期间促进 UAR。 UAR 缺陷会损害胎盘 功能，导致胎盘 sFlt-1 表达增加/VEGF 可用性下降，从而 破坏母体全身血管功能。因此，在目标 1C 中，血流动力学将为 在狒狒中进行测定，以检验 E2 诱导 sFlt-1 增加/VEGF 减少的假设 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 妊娠疾病的缺陷以胎儿性别二态性的方式发生，在 Aim 1D UAR 和母亲中 将在怀孕时测定男性和女性胎儿的血管功能，以检验以下假设： 胎儿性别影响后面的过程。虽然 E2 通常会上调 VEGF，但 E2 会降低 EVT VEGF 表达。 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，在目标1E中，我们将培养狒狒EVT来检验ERβ介导的假设 E2 诱导抑制 EVT VEGF 表达、迁移和侵袭。拟议的研究高度 意义重大，因为它重点关注 UAR 的调节，而 UAR 缺陷会导致异常妊娠。这 实验范例和通过 CEU/MB 靶向递送 VEGF/sFlt-1 基因是新颖的前沿 确定 VEGF 对灵长类动物正常和异常 UAR 的作用的方法 对人类的转化应用。阐明 VEGF 对 UAR 的作用将代表着一项重大科学进展 进展并为 VEGF 靶向治疗人类妊娠疾病的应用提供基础。

项目成果

Baboon placental heparin-binding epidermal growth factor-like growth factor.

• DOI: 10.1530/rep-19-0487
• 发表时间: 2020-07
• 期刊: Reproduction (Cambridge, England)
• 作者: Armant DR;Aberdeen GW;Kilburn BA;Pepe GJ;Albrecht ED
• 通讯作者: Albrecht ED

Quantification of Protein Expression by Proximity Ligation Assay in the Nonhuman Primate in Response to Estrogen.

• DOI: 10.1007/978-1-0716-1920-9_6
• 发表时间: 2022
• 期刊: Methods in molecular biology (Clifton, N.J.)

Placental sFlt-1 Gene Delivery in Early Primate Pregnancy Suppresses Uterine Spiral Artery Remodeling.

灵长类动物妊娠早期胎盘 sFlt-1 基因传递抑制子宫螺旋动脉重塑。

• DOI: 10.1210/endocr/bqac012
• 发表时间: 2022
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: Aberdeen,GrahamW;Babischkin,JefferyS;Lindner,JonathanR;Pepe,GeraldJ;Albrecht,EugeneD
• 通讯作者: Albrecht,EugeneD