Hypoxia regulates trophoblast giant cell differentiation

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DESCRIPTION (provided by applicant): Hypertension is a hallmark symptom of a common condition associated with pregnancy, preeclampsia. Maternal hypertension in preeclampsia often develops suddenly and severely. The only effective treatment of this disease is delivery of the fetus and more importantly, the placenta. Thus, the majority of preeclamptic patients must deliver prematurely. The cause of preeclampsia is unknown, but impaired development of the placenta is strongly associated with the condition. The placenta is composed of trophoblast cells. Early in pregnancy, trophoblast cells are proliferative. Upon encountering changes in the intrauterine environment, they differentiate to fulfill particular functions. One subset of trophoblasts acquires an invasive phenotype. Invasive trophoblasts are responsible for remodeling the maternal uterine arteries to obtain blood flow to the rest of the placenta and the growing fetus. In preeclampsia, the invasive trophoblasts fail to properly differentiate. Oxygen is one of the environmental cues postulated to trigger trophoblast differentiation. Previous studies suggest that tropoblast cell differentiation is inhibited by hypoxia, but the molecular mechanisms involved have not been identified. Mammalian cellular responses to low oxygen conditions can be mediated by the transcription factor Hypoxia Inducible Factors (HIFs). We hypothesize that HIFs mediate hypoxic inhibition of trophoblast differentiation. To address this hypothesis, we will determine the effect of hypoxia, HIF-1 alpha, and HIF-2 alpha expression on trophoblast differentiation. Trophoblast differentiation will be assayed by analyzing changes in transcription factor expression, endoreduplication, and invasiveness. The results of these experiments will elucidate if HIFs mediate trophoblast differentiation. Understanding how oxygen signaling mediates trophoblast differentiation will help identify altered mechanisms that could cause preeclampsia.