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.

我们最近表明，在雌激素（E2）抑制的狒狒中传递的后代暴露了胰岛素抵抗，葡萄糖intlerance和第一相胰岛素分泌中的防御，这些步骤逐步发展为2型糖尿病（T2DM）。但是，该E2受调节事件的基础的机制尚不清楚。微血管（MV）单位（即动脉和相关的毛细血管[CAP]）通过使胰岛素和葡萄糖递送到靶组织（尤其是骨骼肌（SM））在胰岛素作用中具有根本重要的作用。但是，在胎儿发育过程中胰岛素目标时机内形成了广泛的MV网络，但是，几乎没有 知道对胎儿中这一至关重要的发展过程的调节。血管生成是 在胎儿发育和血管内皮生长因子-A（VEGF）期间，CAP网络扩展的基础是SM中血管生成的主要调节剂。因此，这项“健康与疾病的发展起源”研究的高度新颖的概念是，子宫内的E2促进了胎儿中的SMM MV发育，因此形成了广泛的MV网络，对于胰岛素和葡萄糖的传递至关重要，因此胰岛素作用和胰岛素作用和胰岛素动作和葡萄糖动作和葡萄糖稳态在SM中的SM中。在AIM 1中，我们将检验以下假设：E2促进狒狒胎儿中SM MV的形态和功能发展，这是导致后代胰岛素敏感性的重要步骤。 SM VEGF表达，盖密度和MV成熟和形态将在胎儿中（第100天）和晚期（第165-175天；术语= 184天）以及在2、3和4岁时的后代在未经治疗或在baboon中抑制E2的生产/水平，让Eampase introz andros andros andros androz androz androz andros andros androze androz androze androze的后代。 SM血管功能将通过臂动脉流介导的词典和CAP流（通过对比增强的超声/微泡技术量化）在后代的后代（后代）之前量化，以量化E2-剥夺/重塑的狒狒。 AIM 2将确定E2在AIM 1中确定的E2促进SM血管生成的机制。我们将测试E2迅速刺激SM VEGF表达的假设，CAP内皮细胞（EC）紧密连接（TJ）/ADHERENS/ADHERENS/ADHERENS OFNCTION（AJ）分解和CAP EC，以及CAP CAP EC 在妊娠第165天的血管生成的早期步骤中，静脉注射E2向letrozole处理的狒狒的胎儿注射E2后，妊娠第165天。拟议的研究具有临床意义，因为早产，芳香酶突变，类固醇硫酸酶缺乏症，雌激素受体无效突变以及母体/胎儿暴露于内分泌干扰物，这些破坏者会使胎儿暴露于E2的正常升高或作用E2的正常高度，与胰岛素抵抗的事件增加了，胰岛素抵抗/T2DM的人类抗刺激性。确立E2对灵长类动物后代中胰岛素敏感性发育和胰岛素敏感性发作的重要性为人类治疗应用提供了基础。