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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). 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
Subjects:	R Medicine > RG Gynecology and obstetrics
Divisions:	Faculty of Medicine > Warwick Medical School > Clinical Sciences Research Institute (CSRI) Faculty of Medicine > Warwick Medical School > Metabolic and Vascular Health Faculty of Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	Preecampsia, Oxidative stress
Journal or Publication Title:	Reproductive Biology and Endocrinology
Publisher:	BioMed Central Ltd.
ISSN:	1477-7827
Date:	15 January 2009
Volume:	Vol.7
Number:	No.4
Identification Number:	10.1186/1477-7827-7-4
Status:	Peer Reviewed
Access rights to Published version:	Open Access
References:	1. MacKay AP, Berg CJ, Atrash HK: Pregnancy-related mortality from preeclampsia and eclampsia. Obstet Gynecol 2001, 97:533-538. 2. Duley L: Maternal mortality associated with hypertensive disorders of pregnancy in Africa, Asia, Latin America and the Caribbean. Br J Obstet Gynaecol 1992, 99:547-553. 3. Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Menacker F, Munson ML: Births: final data for 2003. Natl Vital Stat Rep 2005, 54(2):1-116. 4. Redman CW, Sargent IL: Latest advances in understanding preeclampsia. Science 2005, 308:1592-1594. 5. Banerjee S, Chambers AE, Campbell S: Is Vitamin E a safe prophylaxis for pre-eclampsia? Am J Obstet & Gynecol 2006, 194:1228-1233. 6. Suh YA, Arnold RS, Lassegue B, Shi J, Xu X, Sorescu D, Chung AB, Griendling KK, Lambeth JD: Cell transformation by the superoxide- generating oxidase Mox1. Nature 1999, 401:79-82. 7. Geiszt M, Kopp JB, Varnai P, Leto TL: Identification of Renox, an NAD(P)H oxidase in kidney. Proc Natl Acad Sci USA 2000, 97:8010-8014. 8. Nemoto S, Takeda K, Yu ZX, Ferrans VJ, Finkel T: A role for mitochondrial oxidants as regulators of cellular metabolism. Mol Cell Biol 2000, 20:7311-7318. 9. Liu Y, Zhao H, Li H, Kalyanaraman B, Nicolosi AC, Gutterman DD: Mitochondrial sources of H2O2 generation play a key role in flow-mediated dilation in human coronary resistance arteries. Circ Res 2003, 93:573-580. 10. Zafari AM, Ushio-Fukai M, Akers M, Yin Q, Shah A, Harrison DG, Taylor WR, Griendling KK: Role of NADH/NADPH oxidasederived H2O2 in angiotensin II-induced vascular hypertrophy. Hypertension 1998, 32:488-495. 11. Thaler I, Manor D, Itskovitz J, Rottem S, Levit N, Timor-Tritsch I, Brandes JM: Changes in uterine blood flow during human pregnancy. Am J Obstet Gynecol 1990, 162:121-125. 12. Yi FX, Bird IM: Pregnancy-specific modulatory role of mitochondria on adenosine 5'-triphosphate-induced cytosolic [Ca2+] signaling in uterine artery endothelial cells. Endocrinology 2005, 146:4844-4850. 13. Torbergsen T, Oian P, Mathiesen E, Borud O: Pre-eclampsia – a mitochondrial disease? Acta Obstet Gynecol Scand 1999, 68:145-148. 14. Wang Y, Walsh SW: Placental mitochondria as a source of oxidative stress in pre-eclampsia. Placenta 1998, 9:581-586. 15. Tannetta DS, Sargent IL, Linton EA, Redman CW: Vitamins C and E inhibit apoptosis of cultured human term placenta trophoblast. Placenta 2008, 29:680-690. 16. Melov S, Coskun P, Patel M, Tuinstra R, Cottrell B, Jun AS, Zastawny TH, Dizdaroglu M, Goodman SI, Huang TT, Miziorko H, Epstein CJ, Wallace DC: Mitochondrial disease in superoxide dismutase 2 mutant mice. Proc Natl Acad Sci USA 1999, 96:846-851. 17. Ushio-Fukai M, Tang Y, Fukai T, Dikalov SI, Ma Y, Fujimoto M, Quinn MT, Pagano PJ, Johnson C, Alexander RW: Novel role of gp91phox-containing NAD(P)H oxidase in vascular endothelial growth factor-induced signaling and angiogenesis. Circ Res 2002, 91:1160-1167. 18. Dworakowski R, Alom-Ruiz SP, Shah AM: NADPH oxidasederived reactive oxygen species in the regulation of endothelial phenotype. Pharmacol Rep 2008, 60:21-28. 19. Muzaffar S, Shukla N, Angelini GD, Jeremy JY: Superoxide autoaugments superoxide formation and upregulates gp91(phox) expression in porcine pulmonary artery endothelial cells: inhibition by iloprost. Eur J Pharmacol 2006, 538:108-114. 20. Hawkins BJ, Madesh M, Kirkpatrick CJ, Fisher AB: Superoxide flux in endothelial cells via the chloride channel-3 mediates intracellular signaling. Mol Biol Cell 2007, 18:2002-2012. 21. Semenza GL, Wang GL: A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol 1992, 12:5447-5454. 22. Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ: The tumour suppressor protein VHL targets hypoxia inducible factors for oxygen-dependent proteolysis. Nature 1999, 399:271-275. 23. Bruick RK, McKnight SL: A conserved family of prolyl-4-Hydroxylases that modify HIF. Science 2001, 294:1337-1340. 24. Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O'Rourke J, Mole DR, Mukherji M, Metzen E, Wilson MI, Dhanda A, Tian YM, Masson N, Hamilton DL, Jaakkola P, Barstead R, Hodgkin J, Maxwell PH, Pugh CW, Schofield CJ, Ratcliffe PJ: C. elegans EGL-9 and mammalian homologues define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 2001, 107:43-54. 25. Pagé EL, Chan DA, Giaccia AJ, Levine M, Richard DE: Hypoxiainducible factor-1alpha stabilization in nonhypoxic conditions: role of oxidation and intracellular ascorbate depletion. Mol Biol Cell 2008, 19:86-94. 26. Chandel NS, McClintock DS, Feliciano CE, Wood TM, Melendez JA, Rodriguez AM, Schumacker PT: Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O2 sensing. J Biol Chem 2000, 275:25130-25138. 27. Gerald D, Berra E, Frapart YM, Chan DA, Giaccia AJ, Mansuy D, Pouyssegur J, Yaniv M, Mechta-Grigoriou F: JunD reduces tumor angiogenesis by protecting cells from oxidative stress. Cell 2004, 118:781-794. 28. Bell EL, Klimova TA, Eisenbart J, Moraes CT, Murphy MP, Budinger GR, Chandel NS: The Qo site of the mitochondrial complex III is required for the transduction of hypoxic signaling via reactive oxygen species production. J Cell Biol 2007, 177:1029-1036. 29. Pan Y, Mansfield KD, Bertozzi CC, Rudenko V, Chan DA, Giaccia AJ, Simon MC: Multiple factors affecting cellular redox status and energy metabolism modulate hypoxia-inducible factor prolyl hydroxylase activity in vivo and in vitro. Mol Cell Biol 2007, 27:912-925. 30. Kanayama N, Takahashi K, Matsuura T, Sugimura M, Kobayashi T, Moniwa N, Tomita M, Nakayama K: Deficiency in p57Kip2 expression induces preeclampsia-like symptoms in mice. Mol Hum Reprod 2002, 8:1129-1135. 31. Hoffmann DS, Weydert CJ, Lazartigues E, Kutschke WJ, Kienzle MF, Leach JE, Sharma JA, Sharma RV, Davisson RL: Chronic tempol prevents hypertension, proteinuria, and poor feto-placental outcomes in BPH/5 mouse model of preeclampsia. Hypertension 2008, 51:1058-1065. 32. Kanasaki K, Palmsten K, Sugimoto H, Ahmad S, Hamano Y, Xie L, Parry S, Augustin HG, Gattone VH, Folkman J, Strauss JF, Kalluri R: Deficiency in catechol-O-methyltransferase and 2-methoxyoestradiol is associated with pre-eclampsia. Nature 2008, 453:1117-1121. 33. Carter AM: Animal models of human placentation-a review. Placenta 2007, 28(Suppl A):S41-S47. 34. Adamson SL, Lu Y, Whiteley KJ, Holmyard D, Hemberger M, Pfarrer C, Cross JC: Interactions between trophoblast cells and the maternal and fetal circulation in the mouse placenta. Dev Biol 2002, 250:358-373. 35. Redline RW, Lu CY: Localization of fetal major histocompatibility complex antigens and maternal leukocytes in murine placenta. Implications for maternal-fetal immunological relationship. Lab Invest 1989, 61:27-36. 36. Pijnenborg R, Vercruysse L, Hanssens M: The uterine spiral arteries in human pregnancy: facts and controversies. Placenta 2006, 12:939-958. 37. Malassine A, Frendo JL, Evain-Brion D: A comparison of placental development and endocrine functions between the human and mouse model. Hum Reprod Update 2003, 9:531-539. 38. Martin RD: Human reproduction: a comparative background for medical hypotheses. J Reprod Immunol 2003, 59:111-135. 39. Huang P, Feng L, Oldham EA, Keating MJ, Plunkett W: Superoxide dismutase as a target for the selective killing of cancer cells. Nature 2000, 407:390-395. 40. Wang M, Kirk JS, Venkataraman S, Domann FE, Zhang HJ, Schafer FQ, Flanagan SW, Weydert CJ, Spitz DR, Buettner GR, Oberley LW: Manganese superoxide dismutase suppresses hypoxic induction of hypoxia-inducible factor-1alpha and vascular endothelial growth factor. Oncogene 2005, 24:8154-8166. 41. Berg D, Sonsalla R, Kuss E: Concentrations of 2-methoxyoestrogens in human serum measured by a heterologous immunoassay with an 125I-labelled ligand. Acta Endocrinol (Copenh) 1983, 103:282-288. 42. Sugawara J, Mitsui-Saito M, Hoshiai T, Hayashi C, Kimura Y, Okamura K: Circulating endothelial progenitor cells during human pregnancy. J Clin Endocrinol Metab 2005, 90:1845-1848. 43. Wood L, Leese MR, Leblond B, Woo LW, Ganeshapillai D, Purohit A, Reed MJ, Potter BV, Packham G: Inhibition of superoxide dismutase by 2-methoxyoestradiol analogues and oestrogen derivatives: structure-activity relationships. Anticancer Drug Des 2001, 16:209-215. 44. Pelicano H, Feng L, Zhou Y, Carew JS, Hileman EO, Plunkett W, Keating MJ, Huang P: Inhibition of mitochondrial respiration: a novel strategy to enhance drug-induced apoptosis in human leukemia cells by a reactive oxygen species-mediated mechanism. J Biol Chem 2003, 278:37832-37839. 45. Golab J, Nowis D, Skrzycki M, Czeczot H, Baranczyk-Kuzma A, Wilczynski GM, Makowski M, Mroz P, Kozar K, Kaminski R, Jalili A, Kopec M, Grzela T, Jakobisiak M: Antitumor effects of photodynamic therapy are potentiated by 2-methoxyestradiol. A superoxide dismutase inhibitor. J Biol Chem 2003, 278:407-414. 46. Moser C, Lang SA, Mori A, Hellerbrand C, Schlitt HJ, Geissler EK, Fogler WE, Stoeltzing O: ENMD-1198, a novel tubulin-binding agent reduces HIF-1alpha and STAT3 activity in human hepatocellular carcinoma(HCC) cells, and inhibits growth and vascularization in vivo. BMC Cancer 2008, 8:206. 47. Cramer T, Yamanishi Y, Clausen BE, Förster I, Pawlinski R, Mackman N, Haase VH, Jaenisch R, Corr M, Nizet V, Firestein GS, Gerber HP, Ferrara N, Johnson RS: HIF-1alpha is essential for myeloid cellmediated inflammation. Cell 2003, 112:645-657. 48. Peyssonnaux C, Cejudo-Martin P, Doedens A, Zinkernagel AS, Johnson RS, Nizet V: Cutting edge: Essential role of hypoxia inducible factor-1alpha in development of lipopolysaccharideinduced sepsis. J Immunol 2007, 178:7516-7519. 49. Lamond S, Watkinson M, Rutherford T, Laing K, Whiting A, Smallwood A, Nargund G, Campbell S, Banerjee S: Gene-specific chromatin damage in human spermatozoa can be blocked by antioxidants that target mitochondria. Reprod Biomed Online 2003, 7:407-418.
URI:	http://wrap.warwick.ac.uk/id/eprint/521