Mechanisms of Preeclampsia Risk with Obesity: Role of Elevated ADMA

描述（由申请人提供）：妊娠特异性综合征先兆子痫是孕产妇和胎儿发病率和死亡率的主要原因。先兆子痫的根本原因尚不清楚，然而，几种预先存在的母体疾病与先兆子痫的风险增加相关，包括：糖尿病，高血压，肾功能不全和肥胖。在这些病症中，肥胖症在人群中一直在增加，并且肥胖症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，肥胖独立地增加先兆子痫的风险，以及最近的证据表明，怀孕之间母亲体重的增加也与先兆子痫风险的显着增加有关。然而，关于肥胖和成人体重增加增加先兆子痫风险的机制研究很少。多项证据表明，内皮功能障碍是先兆子痫病理生理学的中心特征，内皮功能障碍是肥胖的常见终点。不对称二甲基精氨酸（ADMA）是一氧化氮合酶（NOS）的内源性抑制剂，升高的ADMA会导致内皮功能障碍，ADMA会对血管生成、内皮祖细胞动员和活性产生负面影响，ADMA会损害滋养层侵袭（所有活动在妊娠中都很重要，在先兆子痫中缺乏），ADMA在肥胖症中升高，ADMA在后来发展为先兆子痫的女性中在妊娠早期升高。因此，本提案的重点将是研究ADMA升高的作用，作为肥胖导致血管功能、血管生成、内皮祖细胞数量和功能以及妊娠期间滋养层细胞迁移和侵袭改变的机制。我们将调查的作用，ADMA对这些活动在怀孕中使用特定的小鼠模型的高和低ADMA的存在和不存在肥胖。肥胖是妊娠期血管疾病先兆子痫的一个重要危险因素.内源性一氧化氮合酶抑制剂ADMA在肥胖和先兆子痫中升高。升高的ADMA对血管功能、血管生成和滋养层浸润产生负面影响，因此可能是肥胖增加先兆子痫风险的重要机制。公共卫生相关性：肥胖是妊娠并发症先兆子痫的单一最重要的风险因素，占影响所有孕妇5%的综合征病例的15%至32%，然而肥胖影响这种风险的机制尚不清楚。该项目的重点是研究ADMA升高作为肥胖损害内皮依赖性血管功能、血管生成和滋养层侵袭的机制的作用，这些功能在正常妊娠中都很重要，在先兆子痫中受到损害，并受到ADMA的负面影响。

DESCRIPTION (provided by applicant): 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 independently increases the risk of preeclampsia as well as recent evidence showing that increases in maternal weight between pregnancies are also associated with a significant increase in the risk of preeclampsia. However, there has been little investigation of the mechanisms by which obesity and adult weight gain increase preeclampsia risk. 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, ADMA impairs trophoblast invasion (all 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. Public Health Relevance: Obesity is the single most significant risk factor for the pregnancy complication preeclampsia, accounting for 15 to 32% of the cases of the syndrome that affects 5% of all pregnant women, however the mechanism by which obesity influences this risk is unknown. The focus of this project is to investigate the role of elevated ADMA as a mechanism by which obesity impairs endothelial-dependent vascular function, angiogenesis and trophoblast invasion which are all important in normal pregnancy, impaired in preeclampsia and negatively affected by ADMA.