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.
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