For the last several years, our laboratory has investigated the role of glucocorticoid (GC) in the periparturitional regulation of ECM proteins in the placenta and fetal membranes in humans and non-human primates. In this application, we test a novel action of GC, its role in promoting placental damage in pregnancies associated with intrauterine growth restriction and preeclampsia (IUGR/PE). Based on our preliminary results, we hypothesize that GC, induced in response to fetal stress, promotes an antifibrinolytic/promatrix placental state by pathologically enhancing the expression of plasminogen activator inhibitor-i (PAl- 1) in syncytiotrophoblasts (SYNCTs) and ECM proteins in placental mesenchymal cells (PMCs). We postulate that this hypermatrix state in placenta reduces the flow of nutrients between mother and fetus and compromises fetal well-being. To test this hypothesis we will: 1) use primary cultures of SYNCTs to examine the effect of GC treatment on the stability of PAl-1 mRNA and the expression of proteins that bind to the 3'-untranslated region of the PAl- 1 gene and alter mRNA stability; 2) use run-on and zymographic assays to evaluate the mechanism of GC-mediated over-expression of basal laminar and interstitial ECM proteins in primary cultures of PMCs; 3) determine whether fibrinolytic parameters and levels of ECM proteins are coordinately altered in IUGR/PE placentas compared to controls matched for gestational age; 4) use an in vivo baboon model to determine whether a single or a triple dose of betamethasone (BM) alters placental gene expression in a manner that mimics the anti-fibrinolytic/promatrix state that is observed in pregnancies associated with IUGR/PE. These studies will shed light on the mechanism through which fetal stress alters placental gene expression in pregnancies with IUGR/PE.
