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）抑制狒狒的后代表现出胰岛素抵抗、葡萄糖耐受不良和第一阶段胰岛素分泌不足，这些步骤进展为2型糖尿病（T2DM）。然而，E2调控事件的机制尚不清楚。微血管（MV）单元（即小动脉和相关毛细血管[cap]）在胰岛素作用中起着至关重要的作用，使胰岛素和葡萄糖能够输送到靶组织，特别是骨骼肌（SM）。在胎儿发育过程中，胰岛素靶组织内形成了广泛的MV网络，然而，这种网络很少