Hypoxia-inducible factors 1α and 2α regulate trophoblast differentiation

摘要: Placental development initially occurs in a low-oxygen (O2) or hypoxic environment. In this report we show that two hypoxia-inducible factors (HIFs), HIF1 and HIF2, are essential for determining murine placental cell fates. HIF is heterodimer composed of (ARNT) subunits. Placentas from Arnt / Hif1 Hif2 embryos exhibit defective vascularization aberrant fate adoption. regulation Mash2 promotes spongiotrophoblast differentiation, prerequisite trophoblast giant differentiation. the absence Hif, stem cells fail to generate these types become labyrinthine trophoblasts instead. Therefore, mediates morphogenesis, angiogenesis, decisions, demonstrating O2 tension critical regulator lineage determination. This novel genetic approach provides new insights into role life-threatening pregnancy-related diseases such as preeclampsia. Defective placentation implicated one causes preeclampsia, pregnancy-associated disease affects 4 5% all births major cause maternal neonatal mortality (49). Women with preeclampsia suffer edema, hypertension, proteinuria. Preeclamptic placentas display shallow invasion cytotrophoblasts (trophectoderm derivatives placenta) uterus, fewer numbers invasive cytotrophoblasts, spiral arteries have not been converted enlarged vessels. These pathologies lead reduced blood flow hypoxia (16, 49). Physiological may also play an important directing development. delineating differentiation during will enable us better understand treat pregnancyrelated diseases. Furthermore, mouse models resulting intrauterine growth retardation allow genetically define pathways involved both pathologies. Murine similar human embryos. The three layers chorioallantoic placenta form between embryonic day 9.0 (E9.0) E10.0. layer closest embryo, layer, develops when fetal vessels allantoic mesoderm invade chorion (Fig. 1A). Fetal vessel instructs chorionic precursors differentiate by fusion syncytiotrophoblasts (38). Labyrinthine interdigitated order facilitate O2, nutrient, waste exchange (14). Trophoblasts polar trophecto