Placental
hypoxia has been implicated in pregnancy pathologies, including
fetal growth restriction and
preeclampsia; however, the mechanism by which the trophoblast cell responds to
hypoxia has not been adequately explored.
Glucose transport, a process crucial to fetoplacental growth, is upregulated by
hypoxia in a number of cell types. We investigated the effects of
hypoxia on the regulation of trophoblast
glucose transporter (GLUT) expression and activity in BeWo
choriocarcinoma cells, a trophoblast cell model, and human placental villous tissue explants. GLUT1 expression in BeWo cells was upregulated by the
hypoxia-inducing chemical agents
desferroxamine and
cobalt chloride. Reductions in
oxygen tension resulted in dose-dependent increases in GLUT1 and GLUT3 expression. Exposure of cells to hypoxic conditions also resulted in an increase in transepithelial
glucose transport. A role for
hypoxia-inducible factor (HIF)-1 was suggested by the increase in HIF-1alpha as a result of
hypoxia and by the increase in GLUT1 expression following treatment of BeWo with
MG-132, a proteasomal inhibitor that increases HIF-1 levels. The function of HIF-1 was confirmed in experiments where the hypoxic upregulation of GLUT1 and GLUT3 was inhibited by antisense HIF-1alpha. In contrast to BeWo cells,
hypoxia produced minimal increases in GLUT1 expression in explants; however, treatment with
MG-132 did upregulate syncytial basal membrane GLUT1. Our results show that GLUTs are upregulated by
hypoxia via a HIF-1-mediated pathway in trophoblast cells and suggest that the GLUT response to
hypoxia in vivo will be determined not only by low
oxygen tension but also by other factors that modulate HIF-1 levels.