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Mouse models for preeclampsia: disruption of redox-regulated signaling
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Banerjee, Subhasis, Randeva, Harpal S. and Chambers, Anne E. (2009) Mouse models for preeclampsia: disruption of redox-regulated signaling. Reproductive Biology and Endocrinology, Vol.7 (No.4). doi:10.1186/1477-7827-7-4 ISSN 1477-7827.
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Official URL: http://dx.doi.org/10.1186/1477-7827-7-4
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-Omethyl 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.
Item Type: | Journal Article | ||||
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Subjects: | R Medicine > RG Gynecology and obstetrics | ||||
Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine > Metabolic and Vascular Health (- until July 2016) Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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Library of Congress Subject Headings (LCSH): | Preecampsia, Oxidative stress | ||||
Journal or Publication Title: | Reproductive Biology and Endocrinology | ||||
Publisher: | BioMed Central Ltd. | ||||
ISSN: | 1477-7827 | ||||
Official Date: | 15 January 2009 | ||||
Dates: |
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Volume: | Vol.7 | ||||
Number: | No.4 | ||||
DOI: | 10.1186/1477-7827-7-4 | ||||
Status: | Peer Reviewed | ||||
Access rights to Published version: | Open Access (Creative Commons) |
Data sourced from Thomson Reuters' Web of Knowledge
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