Maternal Androgen Excess: Vascular and Placental Function and Fetal Consequences

描述（由申请方提供）：妊娠期间母体雄激素水平升高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，还是间接作用于母体，目前尚不清楚。基于我们的初步数据，睾酮不通过胎盘和观察血管和胎盘缺陷的妊娠大鼠与T升高，我们假设，母体T升高损害心血管（CV）的适应和胎盘功能，损害胎儿的发展，从而导致成人疾病的发展。因此，本提案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。具体目标1：描述T升高对母体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T升高会增加母鼠的平均动脉压。问题1b：T升高是否会改变母亲的血管内皮功能？我们假设，一氧化氮（NO）的生产，eNOS的表达，和内皮依赖性血管舒张功能的动脉肠系膜和子宫血管受到影响，在母亲与T升高。问题1c：T母鼠的血管平滑肌（VSM）细胞功能是否改变？我们假设，VSM收缩反应增加肠系膜和子宫血管的T母鼠。具体目标2：研究T升高对胎盘功能的影响。问题2a：母体T升高会导致胎盘功能障碍吗？我们推测，在T治疗的母亲，胎盘重量，特别是迷路区，大小将减少减少，减少促血管生成和增加抗血管生成因子。问题2b：母体T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，特别是考虑到在几种可能导致宫内生长受限的产科病理条件中报告的较高雄激素水平，如先兆子痫、母体PCOS、肥胖、压力和吸烟。此外，怀孕的非洲裔美国母亲有较高的血清T水平和更高的低出生体重婴儿的频率。此外，母体和成人CV功能障碍的最高发生率也集中在这些人群中。我们的大鼠模型为研究母体雄激素升高的不良影响提供了机会，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.