Mechanisms of Preeclampsia Risk with Obesity: Role of Elevated ADMA

妊娠特异性综合征先兆子痫是孕产妇和胎儿发病的主要原因; mortality.先兆子痫的根本原因是未知的，然而，一些预先存在的产妇 与先兆子痫风险增加相关的病症包括：糖尿病、高血压、肾性高血压、高血压。 功能障碍和肥胖。在这些病症中，肥胖症在人口中一直在增加， 具有最大的归因风险，占先兆子痫人群归因风险的15%至32%。 有大量的证据表明，肥胖会增加先兆子痫的风险。然而，不知道如何 肥胖增加先兆子痫的风险，肥胖介导的代谢异常如何与电流相互作用， 先兆子痫发病机制的假说，以及为什么只有一部分肥胖妇女（6-8%）发展 先兆子痫一些证据表明，内皮功能障碍是心脏病的中心特征。 内皮功能障碍是先兆子痫的病理生理学，并且内皮功能障碍是肥胖的常见终点。不对称 二甲基精氨酸（ADMA）是一种内源性一氧化氮合酶（NOS）抑制剂， 导致内皮功能障碍，ADMA负面影响血管生成，内皮祖细胞 动员、活动和滋养层入侵（活动在怀孕中很重要，但在怀孕中缺乏） 先兆子痫），肥胖者ADMA升高， 后来发展为先兆子痫。因此，本建议的重点将是调查高架的作用 ADMA作为肥胖导致血管功能、血管生成 内皮祖细胞的数量和功能以及妊娠期间滋养层细胞的迁移和侵袭。 我们将研究ADMA对这些活动在妊娠中的作用，使用特定的小鼠模型， 和低ADMA在存在和不存在肥胖。短期-肥胖是一个重要的危险因素， 妊娠血管疾病先兆子痫。内源性一氧化氮合酶抑制剂ADMA， 肥胖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 和滋养层侵入，因此可能是肥胖增加风险的重要机制。 先兆子痫

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.