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.
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