Maternal Androgen Excess: Vascular and Placental Function and Fetal Consequences

描述（由申请人提供）：妊娠期间母体雄激素水平升高可导致后代成年后血压升高、血管、生殖和内分泌功能紊乱。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。根据我们的初步数据，睾酮不会穿过胎盘，并观察到T升高的妊娠大鼠血管和胎盘缺陷，我们假设母体T升高损害心血管（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展。因此，本研究的重点是探讨雄激素诱导的母体CV和胎盘功能障碍的机制。提出了两个具体目标。特异性目的1：表征T升高对母体CV功能的影响。问题1a：升高的T是否会改变母亲的血压？我们假设T升高会增加大坝的平均动脉压。问题1b：升高的T是否会改变母亲的血管内皮功能？我们假设，T升高的母亲肠系膜和子宫血管动脉中一氧化氮（NO）的产生、eNOS的表达和内皮依赖性血管舒张剂的功能受到影响。问题1c：血管平滑肌（VSM）细胞功能是否改变？我们假设在T坝的肠系膜和子宫血管中VSM收缩反应增加。特异性目的2：探讨T升高对胎盘功能的影响。问题2a：母体T细胞升高会导致胎盘功能障碍吗？我们推测，在接受t治疗的母亲中，胎盘重量，特别是迷宫区，大小会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少。问题2b：母体T细胞升高是否会改变胎盘的营养转运能力？我们假设T会降低转运蛋白的表达和活性，导致氨基酸和葡萄糖通过胎盘向胎儿的转运减少。这些研究具有重要意义，特别是考虑到在一些可能导致宫内生长受限的产科病理条件下，如先兆子痫、母体多囊卵巢综合征、肥胖、压力和吸烟，雄激素水平较高。此外，怀孕的非裔美国母亲血清T水平较高，婴儿出生体重低的几率也较大。此外，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机会来研究母体雄激素升高的不利影响，这可能有助于改善母体和胎儿的健康。

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.