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 maternalconditions are associated with an increased risk of preeclampsia including: diabetes, hypertension, renaldysfunction, and obesity. Among these conditions, obesity has been increasing in the population and obesityhas 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 howobesity increases the risk of preeclampsia, how obesity-mediated metabolic abberations interact with currenthypotheses of the pathogenesis of preeclampsia, and why only a subset of obese women (6-8%) developpreeclampsia. Several lines of evidence indicate that endothelial dysfunction is a central feature of thepathophysiology of preeclampsia, and endothelial dysfunction is a common endpoint of obesity. Asymmetricdimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS), elevated ADMAcontributes to endothelial dysfunction, ADMA negatively affects angiogenesis, endothelial progenitor cellmobilization and activity and trophoblast invasion (activities important in pregnancy and deficient inpreeclampsia), ADMA is elevated in obesity, and ADMA is elevated early in pregnancy among women wholater develop preeclampsia. Therefore, the focus of this proposal will be to investigate the role of elevatedADMA 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 highand low ADMA in the presence and absence of obesity. Short- Obesity is a significant risk factor for thevascular disorder of pregnancy preeclampsia. The endogenous inhibitor of nitric oxide synthase, ADMA, iselevated in obesity and preeclampsia. Elevated ADMA negatively affects vascular function, angiogenesisand trophoblast invasion and therefore may be an important mechanism by which obesity increases the riskof preeclampsia.
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