Hypoxia-Inducible Factors 1α and 2α Regulate Trophoblast Differentiation

Abstract

ABSTRACT Placental development initially occurs in a low-oxygen (O 2 ) or hypoxic environment. In this report we show that two hypoxia-inducible factors (HIFs), HIF1α and HIF2α, are essential for determining murine placental cell fates. HIF is a heterodimer composed of HIFα and HIFβ (ARNT) subunits. Placentas from Arnt − / − and Hif1α − / − Hif2α −/− 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 Hifα , 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.