Mechanisms of Preeclampsia: Impact of Obesity

描述(申请人提供)：影响所有人群的肥胖大流行有可能显著增加心血管疾病的患病率，包括妊娠综合征先兆子痫(PE)。孕前肥胖会增加PE的风险，包括早期或严重的PE，增加2到3倍。由于育龄妇女肥胖率高，这导致超重和肥胖导致PE的归因风险为25%至50%。此外，肥胖者血管内皮功能受损的代谢环境(胰岛素抵抗、慢性炎症、血脂异常、不对称二甲基精氨酸增加(ADMA；一氧化氮合酶的内源性抑制物))也是我们认为与胎盘不良相互作用的环境，以促进PE的内皮功能障碍。总而言之，我们的数据表明，孕前肥胖是导致PE的主要、可改变的风险。在接下来的5年里，我们建议关注肥胖增加PE风险的机制。新的方法将被用来识别，然后确定PE相关的细胞滋养层细胞基因表达的变化在这些细胞沿着侵袭途径分化时的功能意义(项目I)。在这种情况下，我们发现参与脂质合成或脂质代谢的分子是最受调控的分子之一。我们还将研究患有和不患有PE的肥胖和苗条妇女(项目II-IV)和肥胖的啮齿动物模型(项目IV和V)。项目二检查肥胖的组成部分(代谢、炎症和生活方式)是否与先兆子痫有关，以及这些因素是否汇聚在一起增加ADMA。项目III测试的概念是，与正常妊娠相比，患有PE的妇女，特别是患有PE的肥胖妇女，循环中的母体内皮祖细胞(EPC)的数量和血管生成相关活动受到抑制。项目IV旨在探索髓过氧化物酶和相关的炎症/氧化途径如何与血脂异常相交，从而增加肥胖女性发生PE的风险。核心B的项目II-IV建议通过一项为期3周的L精氨酸补充的随机对照试验，直接检查ADMA和一氧化氮在妊娠早期肥胖女性队列中的作用，并评估血管功能和相关的中间终点。项目V将通过直接研究肥胖和ADMA对血管功能、内皮祖细胞数量和功能、血管生成和滋养层功能的作用来补充项目II。这些协调研究将开始阐明孕前肥胖增加PE风险的机制，以及发生PE的肥胖妇女和没有发生PE的肥胖妇女之间的生物差异。凭借我们的临床前和临床方法、我们的记录以及五个项目之间的许多互动，我们预计下一个资助期将导致将基础知识转化为临床实践。

DESCRIPTION (provided by applicant): The obesity pandemic that affects all segments of the population threatens to dramatically increase the prevalence of cardiovascular disease, including the pregnancy syndrome preeclampsia (PE). Pre-pregnancy obesity increases the risk of PE, including early or severe PE, 2 to 3 fold. With the high prevalence of obesity in reproductive age women, this results in an attributable risk of PE from overweight and obesity of 25 to 50%. Furthermore, the metabolic milieu believed to impair vascular endothelial function in the obese (insulin resistance, chronic inflammation, dyslipidemia, increased asymmetric dimethylarginine (ADMA; an endogenous inhibitor of nitric oxide synthase) is also the milieu we suggest interacts with poor placentation to promote the endothelial dysfunction of PE. Collectively, our data point to maternal pregravid obesity as the major, modifiable, risk contributing to PE. In the next 5 years, we propose to focus on the mechanisms by which obesity increases the risk of PE. Novel approaches will be used to identify, and then determine the functional significance of PE-associated changes in cytotrophoblast gene expression as these cells differentiate along the invasive pathway (Project I). In this context, we find that molecules involved in lipid synthesis or lipid metabolism are among the most highly modulated. We will also study obese and lean women with and without PE (Projects II-IV) and obese rodent models (Projects IV and V). Project II examines components of obesity (metabolic, inflammatory and life style) for association with preeclampsia and whether these converge to increase ADMA. Project III tests the concept that the number and angiogenesis-related activities of circulating, maternal endothelial progenitor cells (EPCs) are suppressed in women with PE compared to normal pregnancy, particularly in obese women with PE. Project IV is designed to explore how myeloperoxidase and related inflammatory/oxidative pathways intersect with dyslipidemia to increase the risk of PE in obese women. Projects II-IV with Core B propose to directly examine the role of ADMA and nitric oxide with a 3 week randomized, controlled trial of L-arginine supplementation in a cohort of obese women during early 2nd trimester, with assessment of vascular function and related intermediate endpoints. Project V will compliment Project II by directly investigating the role of obesity and ADMA on vascular function, EPC number and function, angiogenesis and trophoblast function. These coordinated studies will begin to elucidate the mechanisms by which pre-pregnancy obesity increases the risk of PE, and the biologic differences between obese women who develop PE and obese women who do not develop PE. With our preclinical and clinical approaches, our track record, and the many interactions among the five projects, we expect the next funding period to result in the translation of fundamental knowledge to clinical practice.