Mechanisms of Preeclampsia Risk with Obesity: Role of Elevated ADMA

妊娠特定综合征先兆子痫是母婴发病率的主要原因； 死亡率。先兆子痫的潜在原因尚不清楚，但有几个预先存在的母亲 疾病与先兆子痫的风险增加有关，包括：糖尿病、高血压、肾脏 功能障碍和肥胖。在这些情况中，肥胖在人口中一直在增加，肥胖症 有最大的归因风险，占先兆子痫人群归因风险的15%至32%。 有大量证据表明，肥胖会增加先兆子痫的风险。然而，目前还不清楚是如何 肥胖增加先兆子痫的风险，肥胖介导的代谢紊乱如何与当前 先兆子痫发病机制的假设，以及为什么只有一部分肥胖女性(6-8%)发生 先兆子痫。有几条证据表明，内皮功能障碍是 先兆子痫的病理生理学和内皮功能障碍是肥胖的共同终点。不对称 二甲基精氨酸(ADMA)是一氧化氮合酶(NOS)的内源性抑制物，升高了ADMA 促进内皮功能障碍，ADMA负面影响血管生成，内皮祖细胞 动员和活动与滋养层侵袭(在妊娠中重要的活动和缺乏 先兆子痫)，ADMA在肥胖中升高，在以下情况的女性中怀孕早期ADMA升高 后来发展为先兆子痫。因此，这项提案的重点将是调查高架飞机的作用 ADMA是肥胖导致血管功能、血管生成、 妊娠期间内皮祖细胞的数量和功能与滋养层细胞迁移和侵袭。 我们将使用特定的高血糖小鼠模型来研究ADMA在妊娠期间对这些活动的作用。 在有无肥胖的情况下ADMA较低。短期肥胖是一个重要的风险因素 妊娠期先兆子痫的血管紊乱。一氧化氮合酶的内源性抑制物ADMA是 肥胖症和先兆子痫的发病率升高。ADMA升高对血管功能、血管生成产生负面影响 和滋养层细胞的侵袭，因此可能是肥胖增加风险的重要机制 先兆子痫的症状。

The pregnancy-specific syndrome preeclampsia is a leading cause of maternal and fetal morbidity and ; mortality. The underlying cause of preeclampsia is unknown, however several pre-existing maternal conditions are associated with an increased risk of preeclampsia including: diabetes, hypertension, renal dysfunction, and obesity. Among these conditions, obesity has been increasing in the population and obesity has the largest attributable risk, accounting for 15 to 32% of the population attributable risk for preeclampsia. There is abundant evidence that obesity increases the risk of preeclampsia. However, it is unknown how obesity increases the risk of preeclampsia, how obesity-mediated metabolic abberations interact with current hypotheses of the pathogenesis of preeclampsia, and why only a subset of obese women (6-8%) develop preeclampsia. Several lines of evidence indicate that endothelial dysfunction is a central feature of the pathophysiology of preeclampsia, and endothelial dysfunction is a common endpoint of obesity. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS), elevated ADMA contributes to endothelial dysfunction, ADMA negatively affects angiogenesis, endothelial progenitor cell mobilization and activity and trophoblast invasion (activities important in pregnancy and deficient in preeclampsia), ADMA is elevated in obesity, and ADMA is elevated early in pregnancy among women who later develop preeclampsia. Therefore, the focus of this proposal will be to investigate the role of elevated ADMA as a mechanism by which obesity contributes to alterations in vascular function, angiogenesis, endothelial progenitor cell number and function and trophoblast migration and invasion during pregnancy. We will investigate the role of ADMA on these activities in pregnancy using specific mouse models of high and low ADMA in the presence and absence of obesity. Short- Obesity is a significant risk factor for the vascular disorder of pregnancy preeclampsia. The endogenous inhibitor of nitric oxide synthase, ADMA, is elevated in obesity and preeclampsia. Elevated ADMA negatively affects vascular function, angiogenesis and trophoblast invasion and therefore may be an important mechanism by which obesity increases the risk of preeclampsia.