Mouse models for preeclampsia: disruption of redox-regulated signaling |
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Authors: | Subhasis Banerjee Harpal Randeva Anne E Chambers |
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Institution: | (1) Clinical Sciences Research Institute, University of Warwick, Medical School Building, Gibbet Hill Campus, Coventry, CV4 7AL, UK |
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Abstract: | The concept that oxidative stress contributes to the development of human preeclampsia has never been tested in genetically-defined
animal models. Homozygous deletion of catechol-O-methyl transferase (Comt-/-) in pregnant mice leads to human preeclampsia-like
symptoms (high blood pressure, albuminurea and preterm birth) resulting from extensive vasculo-endothelial pathology, primarily
at the utero-fetal interface where maternal cardiac output is dramatically increased during pregnancy. Comt converts estradiol
to 2-methoxyestradiol 2 (2ME2) which counters angiogenesis by depleting hypoxia inducible factor-1 alpha (HIF-1 alpha) at
late pregnancy. We propose that in wild type (Comt++) pregnant mice, 2ME2 destabilizes HIF-1 alpha by inhibiting mitochondrial
superoxide dismutase (MnSOD). Thus, 2ME2 acts as a pro-oxidant, disrupting redox-regulated signaling which blocks angiogenesis
in wild type (WT) animals in physiological pregnancy. Further, we suggest that a lack of this inhibition under normoxic conditions
in mutant animals (Comt-/-) stabilises HIF-1 alpha by inactivating prolyl hydroxlases (PHD). We predict that a lack of inhibition
of MnSOD, leading to persistent accumulation of HIF-1 alpha, would trigger inflammatory infiltration and endothelial damage
in mutant animals. Critical tests of this hypothesis would be to recreate preeclampsia symptoms by inducing oxidative stress
in WT animals or to ameliorate by treating mutant mice with Mn-SOD-catalase mimetics or activators of PHD. |
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