Maternal Androgen Excess: Vascular and Placental Function and Fetal Consequences

母体雄激素过多：血管和胎盘功能以及胎儿的后果

• 批准号: 8306815
• 负责人: SATHISH KUMAR
• 金额: $ 7.65万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-25 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8306815
• 关键词: Address; Adult; Adverse effects; Affect; African American; Amino Acids; Androgens; Angiogenesis Inhibitors; Angiogenic Factor; Applications Grants; Attention; Blood Pressure; Blood Vessels; Cardiovascular Physiology; Cardiovascular system; Cell physiology; Clinical; Data; Defect; Development; Diagnostic; Discipline of obstetrics; Disease; Endocrine; Endothelium-Dependent Relaxing Factors; Environment; Environmental Risk Factor; Exposure to; Female; Fetal Growth Retardation; Fetus; Frequencies; Functional disorder; Future; Glucose; Grant; Health; Human; Hypertension; Intervention; Labyrinth; Lead; Life; Low Birth Weight Infant; Mesenteric Arteries; Mesentery; Metabolic; Modeling; Mothers; Neurosecretory Systems; Nitric Oxide; Nutrient; Obesity; Organ; Ovarian; Pathologic; Pathology Report; Perinatal Exposure; Pilot Projects; Placenta; Placental Insufficiency; Population; Pre-Eclampsia; Pregnancy; Pregnant Women; Production; Program Development; Proteins; Rattus; Renal function; Renin-Angiotensin System; Reporting; Role; Serum; Signal Transduction; Smoking; Smooth Muscle; Smooth Muscle Myocytes; Steroids; Stress; Sympathetic Nervous System; Syndrome; System; Testosterone; Time; Tobacco smoking; United States National Institutes of Health; Vascular Smooth Muscle; Weight; base; cardiovascular risk factor; embryo/fetus; environmental agent; fetal; improved; in utero; insight; male; maternal cigarette smoking; offspring; pregnant; pressure; prevent; programs; reproductive; response; tool

DESCRIPTION (provided by applicant): Elevated maternal androgen levels during pregnancy programs development of increased blood pressure and vascular, reproductive, and endocrine dysfunction in offspring in adult life. Whether this programming effect is exerted directly on the embryo and fetus, or indirectly via effects on the mother, is unknown. Based on our preliminary data that testosterone does not cross placenta and the observation of vascular and placental defects in pregnant rats with elevated T, we hypothesize that elevated maternal T impairs cardiovascular (CV) adaptations and placental function to compromise the development of the fetus, thereby leading to the development of adult diseases. Thus, the focus of this proposal is to investigate the mechanisms of androgen- induced maternal CV and placental dysfunctions. Two specific aims are proposed. Specific Aim 1: Characterize the influence of elevated T on maternal CV function. Question 1a: Does elevated T alter blood pressure (BP) in the mothers? We hypothesize that elevated T will increase mean arterial pressure in dams. Question 1b: Does elevated T alter vascular endothelial function in mothers? We hypothesize that nitric oxide (NO) production, eNOS expression, and endothelium-dependent vasodilator function in arteries of mesenteric and uterine vasculature is affected in mothers with elevated T. Question 1c: Is vascular smooth muscle (VSM) cell function altered in T dams? We hypothesize that VSM contractile response is increased in mesenteric and uterine vasculature of T dams. Specific Aim 2: Investigate the influence of elevated T on placental function. Question 2a: Does elevated maternal T cause placental dysfunction? We hypothesize that in T-treated mothers, the placental weight, especially labyrinth zone, size will be reduced with decreases in proangiogenic and increases in antiangiogenic factors. Question 2b: Does elevated maternal T alter placental nutrient transport capacity? We hypothesize that T will decrease the expression and activity of transporters, leading to decreased transfer of amino acids and glucose across the placenta to the fetus. These studies are of significance, especially in the view of higher androgen levels reported in several obstetric pathological conditions that may lead to intrauterine growth restriction, such as preeclampsia, maternal PCOS, obesity, stress, and smoking. In addition, pregnant African-American mothers have higher serum T levels and a greater frequency of low-birth-weight babies. Moreover, the highest rates of maternal and adult CV dysfunction are also concentrated in these populations. Our rat model presents an opportunity to investigate the adverse effects of elevated maternal androgens, which may aid in improving maternal and fetal health.

描述（由申请人提供）：在成人生活中后代的血压和血管，生殖和内分泌功能障碍的妊娠计划期间的孕妇雄激素水平升高。该编程效应是否直接施加在胚胎和胎儿上，还是通过对母亲的影响间接发挥作用。根据我们的初步数据，即睾丸激素不会跨胎盘跨胎盘，并且观察到T升高的孕妇大鼠的血管和胎盘缺陷，我们假设升高的母体T会损害心血管（CV）适应和胎盘功能，以损害胎儿的发展，从而导致成人疾病的发育。因此，该建议的重点是研究雄激素诱导的母体CV和胎盘功能障碍的机制。提出了两个具体目标。特定目标1：表征升高t对母体简历功能的影响。问题1a：升高的T是否改变了母亲的血压（BP）？我们假设升高的T将增加大坝中的平均动脉压。问题1b：升高的t会改变母亲的血管内皮功能吗？我们假设一氧化氮（NO）产生，eNOS表达和内皮依赖性的血管扩张剂在肠系膜和子宫血管的动脉中受到T升高的母亲的影响。我们假设在T坝的肠系膜和子宫脉管系统中，VSM收缩反应增加了。特定目标2：研究升高T对胎盘功能的影响。问题2a：升高的产妇会引起胎盘功能障碍吗？我们假设在T处理的母亲中，胎盘的体重，尤其是迷宫区域，大小将随着促血管生成的降低和抗血管生成因子的增加而降低。问题2b：升高的产妇会改变胎盘营养运输能力吗？我们假设T会降低转运蛋白的表达和活性，从而导致氨基酸和葡萄糖在整个胎盘向胎儿的转移减少。这些研究具有重要意义，尤其是在几种产科病理条件下报告的较高雄激素水平的观点，这可能会导致宫内生长限制，例如先兆子痫，母体PCOS，肥胖，肥胖，压力和吸烟。此外，怀孕的非裔美国母亲的血清T水平较高，低出生体重的婴儿频率更高。此外，这些人群也集中在母亲和成人CV功能障碍的最高率。我们的大鼠模型提供了一个机会，可以调查升高的母体雄激素的不良影响，这可能有助于改善孕产妇和胎儿健康。