Many obstetrical complications, including preeclampsia and intrauterine growth retardation (IUGR), two of the more significant causes of maternal and fetal morbidity/mortality, are associated with trophoblast dysfunction and aberrant placental vascular development. However, the molecular mechanisms responsible for these functional defects are poorly understood. Trophoblast normally produces the potent angiogenic growth factor, placenta growth factor (PIGF) and expresses PIGF receptors (flt-1) which function in an autocrine manner to promote proliferation and inhibit apoptosis. Trophoblast PIGF expression is uniquely reduced by hypoxia in vitro and clinical studies show that expression is significantly reduced in preeclampsia. These findings support our hypothesis that aberrant trophoblast production of PIGF contributes to the vascular and trophoblast defects commonly associated with preeclampsia. Despite this clinical importance, the molecular mechanisms regulating PIGF expression in trophoblast are not known. Accordingly, the following specific aims will be used to define the molecular mechanisms that regulate PIGF gene expression in normal and preeclamptic trophoblast.
Aim 1 will characterize regulatory promoter regions responsible for constitutively high PIGF expression in trophoblast and will define regions responsible for the cell type specific expression in trophoblast.
Aim 2 will determine transcriptional and post transcriptional regulatory mechanisms mediated by low oxygen tension and nitric oxide that function to decrease trophoblast PIGF expression.
Aim 3 will investigate functional roles that the mRNA stabilizing proteins, HuR and AUF-1, have in regulating PIGF expression in normal and preeclamptic trophoblast. Results from these studies will provide critical information regarding the ability of trophoblast to constitutively express high levels of PIGF and will produce novel data concerning the molecular mechanisms mediated by hypoxia and nitric oxide which decrease PIGF expression during preeclampsia. Collectively, these aims provide the first comprehensive insights into the molecular mechanisms regulating trophoblast PIGF expression which may provide new therapeutic approaches to reverse the anti-angiogenic and trophoblast apoptotic states associated with perfusion compromised pregnancies.
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