Preeclampsia (PE) is a syndrome affecting about 7 percent of pregnancies. It is characterized by hypertension, proteinuria, and generalized edema. Complications from PE result in high maternal and perinatal morbidity and mortality. In addition to cardiovascular complications seen in PE itself, this syndrome also may be a predictor for later chronic hypertensive disorders. Thus, understanding mechanisms involved in PE will benefit women during pregnancy and in postreproductive years. The peroxisome proliferator activated receptors (PPARs) are a family of nuclear receptors believed to be involved in lipid homeostasis. Recent work has shown that these receptors are activated by several factors frequently associated with dyslipidemia, endothelial cell (EC) activation and abnormal placentation of PE. Additionally, we have determined that PPARgamma is expressed in human umbilical vein endothelial cells (HUVECs) and cytotrophoblasts (CTBs), making these good models to study PPARgamma and its potential role in PE. Therefore, I wish to examine the hypothesis that PPARgamma expression and activation are dysregulated in pregnancies affected by PE.
Specific Aim 1. Analyze the expression of PPARgamma in vivo in both normal and PE pregnancies. Placental bed biopsies from normal and preeclamptic pregnancies will be screened for differences in PPARgamma expression.
Specific Aim 2. Analyze PPARgamma expression and activation using in vitro models of PE. Alterations in PPARgamma expression and activation after exposure to serum from PE and normal pregnant women will be analyzed in EC, cytotrophoblast (CTB), and monocyte cultures.
Specific Aim 3. To determine whether PPARgamma activation alters cellular phenotypes associated with PE. Previously defined markers of PE (triglyceride accumulation, oxLDL receptor regulation) will be analyzed in relation to alterations in PPARgamma activation (determined in Specific Aim 2). These studies will provide a mechanistic insight into the dyslipidemia and EC activation that has been observed in PE.
