Estrogen Regulation of Fetal Microvessel Development During Primate Pregnancy: Impact on Insulin Sensitivity in Offspring

灵长类动物怀孕期间雌激素对胎儿微血管发育的调节：对后代胰岛素敏感性的影响

• 批准号: 10553249
• 负责人: Eugene D. Albrecht
• 金额: $ 70.47万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-22 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10553249
• 关键词: 3 year old; 4 year old; 8 year old; Acute; Adherens Junction; Adipose tissue; Adult; Aromatase; Aromatase Inhibitors; Beds; Biological Assay; Biological Availability; Birth; Birth Weight; Blood Vessels; Blood capillaries; Body Weight; Carrier Proteins; Cell Proliferation; Cells; Defect; Development; Developmental Process; Diabetes Mellitus; Disease; Electron Microscopy; Endocrine Disruptors; Endothelial Cells; Estrogen Receptors; Estrogens; Etiology; Event; Exhibits; Experimental Models; Exposure to; Fetal Development; Fetal Growth Retardation; Fetal Skeleton; Fetus; Foundations; Functional disorder; Glucose; Glucose Intolerance; Glucose Transporter; Growth; Health; Human; Incidence; Injections; Insulin; Insulin Receptor; Insulin Resistance; Intravenous Bolus; Ischemia; Laboratories; Letrozole; Ligation; Liver; Mediating; Microbubbles; Morphology; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Pancreas; Papio; Phase; Population; Pre-Eclampsia; Pregnancy; Premature Birth; Primates; Process; Production; Proteins; Receptor Signaling; Regulation; Research; Research Proposals; Role; Scientific Advances and Accomplishments; Skeletal Muscle; Study models; Technology; Testing; Therapeutic; Tight Junctions; Time; Tissues; VEGFA gene; Vascular Diseases; Vascular Endothelial Cell; Vascular System; X-Linked Ichthyosis; angiogenesis; arteriole; blood glucose regulation; brachial artery; clinically significant; contrast enhanced; density; fetal; glucose metabolism; glucose uptake; in utero; in vivo; indexing; innovation; insulin secretion; insulin sensitivity; nonhuman primate; novel; null mutation; offspring; postnatal; postnatal development; prenatal exposure; prepuberty; ultrasound

We recently showed that offspring delivered to estrogen (E2)-suppressed baboons exhibited insulin resistance, glucose intolerance, and a deficit in first phase insulin secretion, steps that progress to type 2 diabetes mellitus (T2DM). However, the mechanism(s) underpinning this E2 regulated event are unknown. The microvessel (MV) unit (i.e. arterioles and associated capillaries [cap]) has a fundamentally important role in insulin action by enabling insulin and glucose delivery to target tissue, notably skeletal muscle (SM). An extensive MV network forms within insulin target tissues during fetal development, however, little is known about the regulation of this critically important developmental process in the fetus. Angiogenesis is foundational for expansion of the cap network during fetal development and vascular endothelial growth factor-A (VEGF) is a predominant regulator of angiogenesis in SM. Therefore, the over-arching highly novel concept of this “developmental origin of health and disease” study is that E2 in utero promotes SM MV development in the fetus and consequently formation of an extensive MV network critical for the delivery of insulin and glucose to and thus insulin action and glucose homeostasis within SM in the offspring. In Aim 1, we will test the hypothesis that E2 promotes SM MV morphological and functional development in the baboon fetus as an essential step leading to insulin sensitivity in the offspring. SM VEGF expression, cap density and MV maturation and morphology will be quantified in the fetus at mid (day 100) and late (days 165-175; term = 184 days) gestation and in offspring at 2, 3 and 4 years of age delivered to baboons untreated or in which E2 production/levels have been suppressed by maternal administration of the aromatase inhibitor letrozole and restored by letrozole plus E2. SM vascular function will be assessed by brachial artery flow-mediated dilation and by cap flow, as quantified by contrast-enhanced ultrasound/microbubble technology, before/during vasochallenge of offspring delivered to E2-deprived/-replenished baboons. Aim 2 will determine the mechanisms by which E2 acts to promote SM angiogenesis in the fetus as established in Aim 1. We will test the hypothesis that E2 rapidly stimulates SM VEGF expression, cap endothelial cell (EC) tight junction (TJ)/adherens junction (AJ) breakdown, and cap EC proliferation as early steps in angiogenesis on day 165 of gestation 0-24 h after an iv bolus injection of E2 to fetuses of letrozole-treated baboons. The proposed study is clinically significant since preterm birth, aromatase mutation, steroid sulfatase deficiency, estrogen receptor null mutation, and maternal/fetal exposure to endocrine disruptors, which curtail exposure of the fetus to the normal elevation in or action of E2, are associated with increased incidence of insulin resistance/T2DM in human offspring. Establishing the importance of E2 to fetal MV development and onset of insulin sensitivity in primate offspring provides a basis for therapeutic application to the human.

我们最近发现，雌激素 (E2) 抑制的狒狒后代表现出胰岛素抵抗、葡萄糖不耐症和第一阶段胰岛素分泌缺陷，这些都是进展为 2 型糖尿病 (T2DM) 的步骤。这种 E2 调节事件尚不清楚。微血管 (MV) 单位（即小动脉和相关毛细血管 [cap]）通过将胰岛素和葡萄糖输送到体内，在胰岛素作用中发挥着重要作用。在胎儿发育过程中，胰岛素靶组织内形成了广泛的 MV 网络，尤其是骨骼肌 (SM)。 众所周知，胎儿血管生成这一至关重要的发育过程的调节。 血管内皮生长因子 A (VEGF) 是胎儿发育过程中帽网络扩张的基础，并且血管内皮生长因子 A (VEGF) 是 SM 中血管生成的主要调节因子。因此，这项“健康和疾病的发育起源”研究的总体高度新颖的概念是。子宫内的 E2 促进胎儿 SM MV 发育，从而形成广泛的 MV 网络，这对于向后代输送胰岛素和葡萄糖至关重要，从而促进后代 SM 内的胰岛素作用和葡萄糖稳态。在图1中，我们将测试E2促进狒狒胎儿中SM MV形态和功能发育的假设，这是导致后代胰岛素敏感性的重要步骤，将在胎儿中对SM VEGF表达、帽密度和MV成熟和形态进行量化。妊娠中期（第 100 天）和晚期（第 165-175 天；足月 = 184 天）以及 2、3 和 4 岁的后代未经治疗的狒狒或通过母体施用芳香酶抑制剂来曲唑抑制 E2 产生/水平并通过来曲唑加 E2 恢复的狒狒血管功能将通过肱动脉血流介导的扩张和帽血流进行评估，通过对比-定量。增强超声/微泡技术，在将后代交付给缺乏/补充 E2 的狒狒之前/期间。将确定 E2 促进胎儿 SM 血管生成的机制，如目标 1 中所建立的。我们将测试 E2 快速刺激 SM VEGF 表达、帽内皮细胞 (EC) 紧密连接 (TJ)/粘附连接 (AJ) 的假设) 击穿和上限 EC 对来曲唑治疗的狒狒胎儿静脉推注 E2 后 0-24 小时，在妊娠第 165 天时，增殖作为血管生成的早期步骤。这项研究具有临床意义，因为早产、芳香酶突变、类固醇硫酸酯酶缺乏、雌激素受体无效。突变和母体/胎儿暴露于内分泌干扰物（这会减少胎儿暴露于 E2 的正常升高或作用）相关。确定 E2 对胎儿 MV 发育和灵长类后代胰岛素敏感性的重要性，为人类的治疗应用奠定了基础。