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

Placental development initially occurs in a low-oxygen (O-2) or hypoxic environment. In this report we show that two hypoxia-inducible factors (HIFs), HIF alpha and HIF2 alpha, are essential for determining murine placental cell fates. HIF is a heterodimer composed of HIF alpha and HIF beta (ARNT) subunits. Placentas from Arnt(-/-) and Hif1 alpha(-/-) Hif2 alpha(-/-) embryos exhibit defective placental vascularization and aberrant cell fate adoption. HIF regulation of Mash2 promotes spongiotrophoblast differentiation, a prerequisite for trophoblast giant cell differentiation. In the absence of Arnt or Hif alpha, trophoblast stem cells fail to generate these cell types and become labyrinthine trophoblasts instead. Therefore, HIF mediates placental morphogenesis, angiogenesis, and cell fate decisions, demonstrating that O-2, tension is a critical regulator of trophoblast lineage determination. This novel genetic approach provides new insights into the role of O-2, tension in the development of life-threatening; pregnancy-related diseases such as preeclampsia