Mechanisms of Preeclampsia Risk with Obesity: Role of Elevated ADMA

描述（由申请人提供）：妊娠特异性综合征子痫前期是孕产妇和胎儿发病和死亡的主要原因。子痫前期的潜在原因尚不清楚，但一些母体已有的疾病与子痫前期的风险增加有关，包括：糖尿病、高血压、肾功能障碍和肥胖。在这些疾病中，肥胖在人群中呈增加趋势，肥胖的归因风险最大，占子痫前期人群归因风险的15% - 32%。有充分的证据表明，肥胖会增加子痫前期的风险，最近的证据表明，怀孕期间母亲体重的增加也与子痫前期风险的显著增加有关。然而，关于肥胖和成人体重增加增加子痫前期风险的机制研究很少。多项证据表明，内皮功能障碍是子痫前期病理生理的核心特征，而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，ADMA升高有助于内皮功能障碍，ADMA对血管生成、内皮祖细胞动员和活性产生负面影响，ADMA损害滋养细胞侵袭（所有这些活动在妊娠中重要，在子痫前期缺乏），ADMA在肥胖中升高，并且在妊娠早期发生子痫前期的妇女中ADMA升高。因此，本研究的重点将是研究肥胖在妊娠期间影响血管功能、血管生成、内皮祖细胞数量和功能以及滋养细胞迁移和侵袭的ADMA升高的作用机制。我们将研究ADMA在妊娠期间对这些活动的作用，使用存在和不存在肥胖的高和低ADMA的特定小鼠模型。肥胖是妊娠子痫前期血管紊乱的重要危险因素。内源性一氧化氮合酶抑制剂ADMA在肥胖和子痫前期升高。ADMA升高会对血管功能、血管生成和滋养细胞侵袭产生负面影响，因此可能是肥胖增加子痫前期风险的重要机制。公共卫生相关性：肥胖是妊娠并发症子痫前期的唯一最重要的危险因素，占该综合征病例的15%至32%，影响所有孕妇的5%，但肥胖影响这种风险的机制尚不清楚。本项目的重点是研究ADMA升高在肥胖损害内皮依赖性血管功能、血管生成和滋养细胞侵袭的机制中的作用，这些功能在正常妊娠中都很重要，在子痫前期受损，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.