Placental Origins of Preeclampsia: A Global Analysis of Cytrophoblast ...

Magee-Women'S Res Inst And Foundation, Pittsburgh PA

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Abstract

The placenta is a transient organ with remarkable functions. Differentiation of its specialized epithelial cells, termed cytotrophoblasts (CTBs), is an important determinant of both its form and function. Our focus is the pathway that gives rise to the invasive subpopulation of cells. During interstitial invasion, a subset of CTBs commingles with resident decidual and immune cells. During endovascular invasion, these fetal cells invade the maternal blood vessels, which they subsequently line. Together, these two components of CTB invasion anchor the placenta to the uterus and divert uterine blood flow to the intervillous space. Given the complexities involved in this explosive process, it is not surprising that anomalies sometimes occur. Preeclampsia (PE), a syndrome that adversely affects the mother (by altering vascular function) and the fetus (by restricting intrauterine growth), is a prime example. Interstitial and endovascular invasion is shallow, and fewer spiral arteries are modified in toto. Our long-term goal is to elucidate the molecular bases of the placental defects that occur in PE and to explain their relationship to the clinical signs of this syndrome. Previously, we showed that in normal pregnancy CTB invasion is accompanied by a phenotypic switch in which these ectodermal derivatives take on many characteristics of endothelial cells. PE is associated with specific deficits in this program as evidenced by defects in adhesion molecule switching and perturbations in their production of angiogenic substances. Recently, we used an unbiased microarray approach to identify novel pathways that function within the basal plate region where the placenta attaches to the decidua. First, we studied the effects of advancing gestational age on gene expression in this area and then we examined the impact of PE. The results of these experiments revealed a wealth of new information. For example, consistent with the hypotheses to be tested in this program project, lipid pathways are among the most highly modulated in both analyses. In addition, molecules with known patterns of regulation (e.g., CRH in normal pregnancy; leptin and sFlt-1 in PE), were expressed in the expected manner, data that strengthen the importance of our novel findings. Accordingly, we now propose using a microarray approach to analyze the effects of PE on CTB invasion. Specifically, we will isolate the progenitors from affected and control placentas and compare their patterns of gene expression as they differentiate/invade in vitro (Aim 1). Then we will determine the functional significance of the changes we observe (Aim 2). We think that these experiments will yield fundamental new insights into the basic placental defects that lead to PE. Additionally, the results could also have clinical utility in prediction and/or diagnosis of this pregnancy complication, with the identification of potential therapeutic targets another possibility.