Elsevier

Placenta

Volume 24, Issues 2–3, February 2003, Pages 199-208
Placenta

Regular Articles
Impaired Oxygen-dependent Reduction of HIF-1α and -2α Proteins in Pre-eclamptic Placentae

https://doi.org/10.1053/plac.2002.0893Get rights and content

Abstract

Pre-eclamptic (PE) placentae overexpress hypoxia inducible transcription factors-1α and -2α proteins (Biol. Repro. 64: 499–506, 2001; Ibid 1019–1020). Possible explanations include (a) impaired oxygen-dependent reduction, and/or (b) enhanced sensitivity to reduced oxygen. After 18 h equilibration under 21 per cent O2 atmosphere, we subjected villous explants prepared from placentae of normal pregnant (NP) and pre-eclamptic (PE) women (n=8 each) to 4 h of hypoxia (2 per cent oxygen), and then studied the disappearance of HIF-1α and -2α proteins during subsequent oxygenation over 90 min (21 per cent oxygen). The disappearance of these HIF proteins as assessed by Western analysis was significantly impaired in the pre-eclamptic tissues. Even after 18 h equilibration under a 21 per cent O2 atmosphere, and then a further 4 h at 21 per cent O2, HIF-1α and -2α protein expression remained increased in villous explants from PE women (both P< 0.04 vs NP). To address whether chronic hypoxia per se (which is believed to exist in the pre-eclamptic placenta) might contribute to these findings, we subjected villous explants from normal placentae (n=6) to 18 h preincubation under 2 per cent or 21 per cent oxygen prior to subsequent incubation for 4 h at 2 per cent oxygen and then 90 min at 21 per cent oxygen. The time course of disappearance of HIF proteins during oxygenation was similar irrespective of the 2 per cent or 21 per cent preconditioning. To evaluate oxygen sensitivity, we exposed villous explants from NP and PE women (n=6 each) to different oxygen atmospheres for 4 h and measured HIF protein induction. Although the data showed a significant inverse relationship between HIF expression and oxygen concentration, there was no significant difference between the slopes of this relationship for the two groups of women. We conclude that villous explants from PE placentae fail to adequately downregulate HIF protein expression upon oxygenation. This abnormality may contribute to their overexpression in vivo.

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