Placental HIFs as markers of cerebral hypoxic distress in fetal mice

Trollmann R, Strasser K, Keller S, Antoniou X, Grenacher B, Ogunshola OO, Dotsch J, Rascher W, Gassmann M. Placental HIFs as markers of cerebral hypoxic distress in fetal mice. Am J Physiol Regul Integr Comp Physiol 295: R1973-R1981, 2008. First published October 1, 2008; doi:10.1152/ajpregu.00053.2008. -Reduced oxygen supply during the pre- and perinatal period often leads to acquired neonatal brain damage. So far, there are no reliable markers available to assess the hypoxic cerebral damage and the resulting prognosis during the immediate postnatal period. Thus we aimed to determine whether the hypoxia-inducible transcription factors (HIF-1 and HIF-2) and/or their target genes in the placenta represent reliable indicators of hypoxic distress of the developing brain during systemic hypoxia at the end of gestation. To this end, pregnant mice were exposed to systemic hypoxia (inspired O-2 fraction: 6%, 6 h) at gestational day 20. This hypoxic exposure significantly increased HIF-1 alpha and HIF-2 alpha protein levels in brain and placental tissue. Compared with normoxic controls, an increase of HIF-1 alpha-immunoreactive neurons and HIF-2 alpha-positive glial cells and vascular endothelial cells was observed in hypoxic cerebral cortex and hippocampus. In placenta, HIF-1 alpha and HIF-2 alpha were expressed in labyrinthine layer with increased staining intensity during hypoxia compared with normoxia. Significant upregulation of VEGF mRNA and protein in brain and placenta, as well as erythropoietin protein in placenta, indicated activity of the HIF system upon fetal hypoxia. Notably, hypoxia did not affect expression of the HIF target genes inducible nitric oxide synthase and GLUT-1. Taken together, at gestational day 20, systemic hypoxia led to upregulation of HIF-alpha in mouse brain that was temporally paralleled in placenta, implying that alpha-subunits of both HIF-1 and HIF-2 are indeed early markers of hypoxic distress in vivo. If our data reflect the situation in humans, analysis of the placenta will allow early identification of the hypoxic brain distress occurring near birth.