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: 8177474
• 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 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8177474
• 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. PUBLIC HEALTH RELEVANCE: Programming of adult health and disease appears to be dependent upon fetal exposure to various in utero environmental factors. Pilot data from our group have highlighted that exposure in utero to elevated androgens causes low birth weight and adult hypertension and further suggest that cardiovascular dysfunction and placental insufficiency may underlie these effects. This proposal will yield important insights that could aid in the development of effective diagnostic tools and interventions to prevent or decrease maternal cardiovascular risk and associated effects on low birth weight and adverse health consequences in adult life.

描述（由申请人提供）：怀孕期间母体雄激素水平升高会导致后代成年后血压升高以及血管、生殖和内分泌功能障碍。这种编程效应是直接作用于胚胎和胎儿，还是间接作用于母亲，目前尚不清楚。根据睾酮不穿过胎盘的初步数据以及对妊娠大鼠 T 升高时血管和胎盘缺陷的观察，我们假设母体 T 升高会损害心血管（CV）适应和胎盘功能，从而损害胎儿的发育，从而导致成人疾病的发生。因此，本提案的重点是研究雄激素诱导的母体心血管和胎盘功能障碍的机制。提出了两个具体目标。具体目标 1：表征升高的 T 对母体 CV 功能的影响。问题 1a：T 升高是否会改变母亲的血压 (BP)？我们假设升高的 T 会增加水坝的平均动脉压。问题 1b：T 升高是否会改变母亲的血管内皮功能？我们假设，在 T 升高的母亲中，一氧化氮 (NO) 的产生、eNOS 的表达以及肠系膜和子宫脉管系统动脉中内皮依赖性血管舒张功能受到影响。问题 1c：T 母鼠的血管平滑肌 (VSM) 细胞功能是否发生改变？我们假设 T 母鼠的肠系膜和子宫脉管系统中 VSM 收缩反应增强。具体目标 2：研究升高的 T 对胎盘功能的影响。问题 2a：母体 T 升高是否会导致胎盘功能障碍？我们假设，在 T 治疗的母亲中，胎盘重量，尤其是迷路区的大小将随着促血管生成因子的减少和抗血管生成因子的增加而减小。问题 2b：母体 T 升高是否会改变胎盘营养转运能力？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通过胎盘向胎儿的转移减少。这些研究具有重要意义，特别是考虑到几种产科病理状况中雄激素水平较高可能导致宫内生长受限，例如先兆子痫、产妇多囊卵巢综合症、肥胖、压力和吸烟。此外，非洲裔美国孕妇的血清 T 水平较高，低出生体重婴儿的发生率较高。此外，孕产妇和成人心血管功能障碍的最高发生率也集中在这些人群中。我们的大鼠模型提供了一个研究母体雄激素升高的不利影响的机会，这可能有助于改善母体和胎儿的健康。 公共卫生相关性：成人健康和疾病的规划似乎取决于胎儿接触各种子宫内环境因素。我们小组的试点数据强调，在子宫内暴露于升高的雄激素会导致低出生体重和成人高血压，并进一步表明心血管功能障碍和胎盘功能不全可能是这些影响的基础。该提案将产生重要的见解，有助于开发有效的诊断工具和干预措施，以预防或降低孕产妇心血管风险以及对低出生体重和成年后不良健康后果的相关影响。