Mouse models for preeclampsia: disruption of redox-regulated signaling.

Reproductive Biology and Endocrinology : RB&E
Subhasis BanerjeeAnne E Chambers

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 infiltr...Continue Reading

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Citations

Jul 20, 2010·Human Reproduction Update·Laura RienziFilippo Ubaldi
Nov 1, 2012·PloS One·Yi-Chen HsiehUNKNOWN Formosa Stroke Genetic Consortium
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Oct 14, 2020·Reproductive Sciences·Khursheed IqbalMichael J Soares
Oct 16, 2020·Pregnancy Hypertension·Karen Marcela JiménezPaul Laissue

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BETA
ubiquitination

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