Hypoxia, HIF and the placenta

Abstract

Early in mammalian development the placenta, a highly vascularized organ, develops to facilitate exchange of oxygen (O2), nutrients and waste between mother and offspring. This process is intricately regulated by O 2 tension and the hypoxic (low O2) uterine environment. Consequently, the placenta provides an excellent model for understanding the relationship between hypoxia (low O2 tension), organogenesis (organ development) and angiogenesis (blood vessel development). Herein we describe recent research on Hypoxia Inducible Factor (HIF), a heterodimeric transcription factor regulated by hypoxia that is crucial for proper placental development. Complete disruption of HIF signaling through loss of the HIFβ (ARNT) or HIF1α and HIF2α subunits results in improper placental development, characterized by a diminished spongiotrophoblast layer and insufficient chorio/allantoic fusion. Experiments using placental stem cells (TS cells) derived from Hif 1α-/- Hif2α-/- (Hifα-/-) and Arnt-/- mice indicate that there is increased expression of the labyrinthine specific transcription factors GCM and TFEB and a deficiency in the spongiotrophoblast transcription factor Mash2. Furthermore Hifα-/- and Arnt-/- TS cells subjected to differentiating conditions tend to adopt a labyrinthine like syncytial fate, and do not form giant cells or spongiotrophoblasts. These observations demonstrate a crucial role for HIF in the formation of the spongiotrophoblast that is probably regulated by Mash2, and suggest a complex interaction between hypoxia, HIF and Mash2 in the formation of the spongiotrophoblast. ©2006 Landes Bioscience.