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

基本信息

批准号：
9365496
负责人：
Eugene D. Albrecht
金额：
$ 64.02万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-08 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9365496
关键词：
Area Arteries Basal Plate Binding Biological Availability Biology Blood Vessels Blood flow Cells Defect Disease 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 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 VEGFA gene Vascular Diseases Vascular Endothelial Cell Vascular Endothelial Growth Factor B Vascular Endothelial Growth Factors 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 targeted delivery trophoblast

项目摘要

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.

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 受损是妊娠疾病的基础，例如胎儿生长受限和先兆子痫 (PE)，从而导致在孕产妇和新生儿的离线发病率/死亡率中，过多的 UAR（如植入胎盘）会损害。尽管 UAR 对成功妊娠的重要性人们却知之甚少。 UAR 调节。使用狒狒作为非人类灵长类动物的翻译模型，我们已经证明了这一点。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，我们提出：（a）E2水平低。妊娠早期促进 EVT VEGF 表达和 UAR 以及 (b) 妊娠中期 E2 的增加因为 E2 对 UAR 的抑制仅与 A 相关。 EVT VEGF 表达减少，目前尚不清楚 VEGF 是否介导这一过程，因此，在 Aims 中。 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 基因对未经处理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，从而母体全身血管功能受到破坏，因此，在目标 1C 中，血流动力学将受到影响。在狒狒中进行测定，以检验 E2 诱导 sFlt-1 增加/VEGF 减少的假设由于胎盘功能障碍和血管的生物利用度导致全身母体血管功能障碍。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：胎儿性别影响后一过程，尽管 E2 通常上调 VEGF，但 E2 会降低 EVT VEGF。 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诱导的EVT VEGF表达、迁移和侵袭抑制是高度的。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。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 的作用的方法阐明 VEGF 对 UAR 的作用将是一项重大科学成果。进展并为 VEGF 靶向治疗人类妊娠疾病的应用提供基础。