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: 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
• 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

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：在人类早期怀孕期间，占地额外的滋养细胞（EVT） 重塑子宫螺旋动脉（UAR），以促进子宫血流和胎儿发育。 UAR损害的基础妊娠障碍，例如胎儿生长限制和先兆子痫（PE），这会导致 在孕产妇和新生儿发病率/死亡率中。相反，多余的UAR，如Pleceta Accreta中，会损害 输送后的血管调节。尽管UAR对成功怀孕很重要，但对 UAR调节。使用狒狒作为非人类灵长类动物翻译模型，我们已经表明 从第二个中学到雌二醇的激增（E2）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的低水平 头三个月促进了EVT VEGF表达和UAR，并且（b）妊娠中期E2的增加 通过抑制EVT VEGF来抑制UAR。因为E2对UAR的抑制只是与 VEGF表达的降低，尚不清楚VEGF是否介导了这一过程。因此，目标 1a，b我们建议使用对比度增强超声（CEU）/微泡（MB）靶向验证VEGF E2处理的狒狒的胎盘基板和抑制VEGF的SFLT-1基因的基因 生物利用度未经治疗的狒狒测试VEGF的假设：（a）介导E2诱导的 在正常怀孕期间抑制UAR和（B）会促进UAR。 UAR中的缺陷损害位置 功能，导致位置SFLT-1表达/VEGF可用性下降的增加，因此 孕产妇全身血管功能的破坏。因此，在AIM 1C中，血流动态将是 在狒狒中确定以下假设，即E2诱导的SFLT-1/VEGF降低的增加 生物利用度导致母体全身性血管功能障碍。因为位置功能障碍和血管 妊娠障碍的缺陷以胎儿性二态性方式发生，AIM 1D UAR和母体 血管功能将在男性和女性胎儿的怀孕中确定，以检验以下假设 胎儿性别会影响以后的过程。尽管E2通常会上调VEGF，但E2降低了EVT VEGF 表达。 E2在VEGF表达中的发散作用可能反映了雌激素接收器的表达/作用 （ER）α与ERβ。因此，在AIM 1E中，我们将培养狒狒EVT，以检验ERβ培养基的假设 E2诱导的EVT VEGF表达，迁移和入侵的抑制。拟议的研究高度 重要的是，它重点是对UAR的调节，而UAR有缺陷的妊娠异常。这 实验范式和通过CEU/MB的靶向传递VEGF/SFLT-1基因是新型的尖端 将确定VEGF对正常和异常UAR的作用的方法 翻译对人类的应用。阐明VEGF对UAR的作用将代表主要的科学 提前并为VEGF靶向在人类妊娠疾病中的治疗应用提供基础。