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NDT Advance Access published online on November 27, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn534
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Low catechol-O-methyltransferase and 2-methoxyestradiol in preeclampsia: more than a unifying hypothesis*

Duska Dragun and Anja Haase-Fielitz

Department of Nephrology and Intensive Care Medicine, Charité University Hospital, Campus Virchow Clinic, Berlin, Germany

Correspondence and offprint requests to: Duska Dragun, Clinic for Nephrology and Intensive Care Medicine, Charité CVK, Augustenburger Platz 1, 13353 Berlin, Germany. Tel: +49-30450653485; Fax: +49-3045055916; E-mail: duska.dragun{at}charite.de

Keywords: angiogenesis; catecholestradiols; maternal syndrome; preeclampsia

Preeclampsia is a systemic disorder of pregnancy characterized by widespread maternal endothelial dysfunction. Clinical manifestations of preeclampsia include placental hypoxia, hypertension, proteinuria and fluid retention. The condition is common and affects over 5% of all pregnancies, thus remaining a leading cause of maternal and fetal morbidity and mortality worldwide [1]. Pregnancies complicated by preeclampsia are associated with greater risk and earlier onset of cardiovascular disease in both mother and infant [2,3]. Preeclampsia originates in the placenta, as it may occur only in the presence of placenta or a hydatiform mole and resolves dramatically postpartum after the delivery of the placenta. Generalized endothelial dysfunction resulting in vasoconstriction and end-organ ischaemia is attributed in all of the clinical aspects of the maternal syndrome in preeclampsia. Search for a unique circulating factor [4] resulted in an identification of multiple factors of endothelial dysfunction, activation and oxidative stress. A major breakthrough was achieved during the past five years by a series of experimental and clinical studies from Karumanchi and associates implicating that changes in circulating angiogenic factors play a decisive role in the pathogenesis of preeclampsia (reviewed in [5]). Increased expression of soluble fms-like tyrosine kinase 1 (sFlt1), a variant of the membrane-bound vascular endothelial growth factor (VEGF)-receptor 1 that consists of the extracellular ligand-binding domain, was associated with decreased placental growth factor (PIGF) and VEGF signalling and consecutive defective angiogenesis [6]. Soluble Flt1 acts as a natural antagonist of the circulating VEGF and increases from mid-gestation onwards, to reach the peak 5–8 weeks before the onset of the maternal syndrome [7]. Soluble endoglin, a circulating coreceptor that may inhibit transforming growth factor-β1 signalling, has properties similar to those of sFlt1 [8]. The excess sFlt1 contributed to various features of the maternal syndrome such as placental hypoxia with placental insufficiency or renal glomerular endotheliosis [5]. Thus, sFlt1 held a promise to fulfil the expectations of the ‘mysterious circulating factor’, as it linked placenta with various features of the maternal endothelial dysfunction. Another aspect of preeclampsia are immune-mediated mechanisms, as autoantibodies agonistic to the angiotensin II type 1 receptor (AT1R) were found in the circulation of preeclamptic women [9]. The autoantibodies were later linked to oxidative stress, increased inflammation and shallow placentation (reviewed in [10]). Finally, introduction of IgG from preeclamptic women targeting AT1R was found to increase the production of sFlt1 in the placenta [11]. Nonetheless, not all women with preeclampsia have increased sFlt1 and/or endoglin concentrations. Even fewer of them develop autoantibodies against AT1R. Thus, there are several unanswered questions concerning the present view of preeclampsia pathogenesis, implicating that additional synergistic factors elaborated by the placenta may be capable of inducing a generalized endothelial dysfunction.

The recent work of K. Kanasaki and associates performed under the aegis of R. Kalluri and published recently in Nature in June this year seems to provide a foundation for the unifying hypothesis on the pathogenesis of preeclampsia [12]. The authors demonstrated that pregnant mice deficient in catechol-O-methyltransferase (COMT) develop multiple functional and structural features of preeclampsia-like phenotype. COMT-deficient mice delivered preterm with higher wastage of fetuses and showed a higher blood pressure and a higher urinary albumin excretion in comparison with wild-type mice [12]. The arteriopathy of the placenta in the COMT-deficient mice resembled human decidual vascular lesion, and glomerular endotheliosis was also present. Levels of hypoxia-inducible factor-1{alpha} (HIF-1{alpha}) protein were higher in the placenta and the sFlt1 plasma concentrations were significantly higher in pregnant COMT-deficient mice compared to controls. Administration of 2-methoxyestradiol (2-ME) rescued the COMT-deficient mice from the preeclampsia-like syndrome without toxicity. Moreover, 2-ME ameliorated placental hypoxia by inhibition of HIF-1{alpha} expression and precluded sFlt1 elevation [12]. Schematic view of how COMT–2-ME interactions contribute to the pathogenesis of maternal syndrome in preeclampsia is provided in Figure 1. In parallel, 2-ME was elevated during the third trimester of normal human pregnancies, while in contrast, the levels of COMT and 2-ME were lower in women with severe preeclampsia. These observations were confirmed by the pharmacologic study, in which the inhibition of COMT induced manifestations of preeclampsia in normal pregnant mice, resembling the COMT-deficient pregnancy phenotype [12]. Administration of 2-ME prevented the increase in blood pressure and occurrence of proteinuria. The protective effect of 2-ME was again attributed to resolution of the hypoxia-induced disruption of the angiogenic balance. Finally, normal pregnant mice developed preeclampsia when given an inhibitor of a precursor of the 2-ME protein. Taken together, 2-ME, generated in the placenta by COMT, not only protects against generalized endothelial dysfunction, but also suppresses sFlt1. Thus, the missing pieces in the preeclampsia puzzle connecting angiogenic disequilibrium with generalized endothelial dysfunction, and the placental insufficiency seem to be found.


Figure 1
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  		Fig. 1
 
Methoxyestradiols are major endogenous metabolites of estradiol [13] with no affinity to oestrogen receptors [14]. Estradiol is metabolized to hydroxyestradiol by cytochorme P450 enzymes and hydroxyestradiol is methylated by COMT to 2-ME [14]. Normally, catecholamines do not interfere with the metabolism of estradiol to 2-ME, yet production of 2-ME may be seriously compromised in cardiovascular pathologies associated with an increased release of catecholamines. Sympathetic activation with increased concentrations of circulating catecholamines and generalized vascular constriction are present in preeclampsia [15]. Catecholamines compete with catecholestradiols for COMT-induced methylation, which results in an impaired metabolization towards 2-ME. There are multiple implications of these findings that may affect clinical management of preeclampsia, in particular, in terms of more precise assessment of risk pregnancies. Thus, 2-ME may have importance as a plasma and urine diagnostic marker of preeclampsia but may also serve as a therapeutic supplement to prevent or treat preeclampsia, as well as some other cardiovascular or renal conditions. While linking COMT to 2-ME provides greatly advances our knowledge in terms of the pathogenesis of preeclampsia, the protective role of 2-ME in cardiovascular and renal pathologies is not completely new. It has been shown that 2-ME acts inhibitorily on proliferation, migration and growth of vascular smooth muscle, endothelial cells and mesangial cells [14,16,17]. Compared to men and postmenopausal women, premenopausal women are relatively protected against various cardiovascular and renal pathologies. Better definition for COMT- and 2-ME-related mechanisms should help us to understand sex-specific differences in renal disease pathogenesis and progression beyond oestrogen-receptor-associated actions. The activity of COMT is controlled by an autosomal dominant inherited functional polymorphism that encodes for the low, high and intermediate activity of the enzyme [18]. Genetically determined COMT activity is not only critically involved in the regulation of affective mood and pain perception [19], but also influences outcomes in patients with ischaemic heart disease [20], implicating that the carriers of the low-activity COMT genotype seem to be susceptible to various stressors. The stage for the COMT–2-ME couple is set in the renal and cardiovascular arena, and we should eagerly await new contributions.

Conflict of interest statement. None declared.



   Notes
 
* Comment on Kanasaki K, Palmsten K, Kalluri R et al. Deficiency in catechol-O-methyltransferase and 2-methoxyoestradiol is associated with pre-eclampsia. Nature 2008; 453: 1117–1121. Back



   References
Top
 References
 

  1. Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet (2005) 365:785–799.[Web of Science][Medline]
  2. Wilson BJ, Watson SM, Prescott GJ, et al. Hypertensive diseases of pregnancy and risk of hypertension and stroke in later life: results from cohort study. BMJ (2003) 326:1–7.[Abstract/Free Full Text]
  3. Hack M, Flannery DJ, Schluchter M, et al. Outcomes in young adulthood of very low birth-weight infants. N Engl J Med (2002) 346:149–151.[Abstract/Free Full Text]
  4. Roberts JM, Taylor RN, Musci TJ, et al. Preeclampsia: an endothelial cell disorder. Am J Obstet Gynecol (1989) 161:1200–1204.[Web of Science][Medline]
  5. Maynard SE, Epstein FH, Karumanchi SA. Preeclampsia and angiogenic imbalance. Annu Rev Med (2008) 59:61–78.[CrossRef][Web of Science][Medline]
  6. Maynard SE, Min JY, Merchan J, et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest (2003) 111:649–658.[CrossRef][Web of Science][Medline]
  7. Levine RJ, Maynard SE, Qian C, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med (2004) 350:672–683.[Abstract/Free Full Text]
  8. Levine RJ, Lam C, Qian C, et al. Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. N Engl J Med (2006) 355:992–1005.[Abstract/Free Full Text]
  9. Wallukat G, Homuth V, Fischer T, et al. Patients with preeclampsia develop agonistic autoantibodies against the angiotensin AT1 receptor. J Clin Invest (1999) 103:945–952.[Web of Science][Medline]
  10. Herse F, Staff AC, Hering L, et al. AT1 receptor autoantibodies and uteroplacental RAS in pre-eclampsia and pregnancy. J Mol Med (2008) 86:697–703.[CrossRef][Web of Science][Medline]
  11. Zhou CC, Ahmad S, Mi T, et al. Autoantibody from women with preeclampsia induces soluble Fms-like tyrosine kinase-1 production via angiotensin type 1 receptor and calcineurin/nuclear factor of activated T-cells signaling. Hypertension (2008) 51:1010–1019.[Abstract/Free Full Text]
  12. Kanasaki K, Palmsten K, Kalluri R, et al. Deficiency in catechol-O-methyltransferase and 2-methoxyoestradiol is associated with pre-eclampsia. Nature (2008) 453:1117–1121.[CrossRef][Web of Science][Medline]
  13. Fotsis T, Zhang Y, Pepper MS, et al. The endogenous oestrogen metabolite 2-methoxyoestradiol inhibits angiogenesis and suppresses tumour growth. Nature (1994) 368:237–239.
  14. Dubey RK, Gillespie DG, Zacharia LC, et al. Methoxyestradiols mediate the antimitogenic effects of estradiol on vascular smooth muscle cells via estrogen receptor-independent mechanisms. Biochem Biophys Res Commun (2000) 278:27–33.[CrossRef][Web of Science][Medline]
  15. Schobel HP, Fischer T, Heuszer K, et al. Preeclampsia—a state of sympathetic overactivity. N Engl J Med (1996) 335:1480–1485.[Abstract/Free Full Text]
  16. Dubey RK, Gillespie DG, Keller PJ, et al. Role of methoxyestradiols in the growth inhibitory effects of estradiol on human glomerular mesengial cells. Hypertension (2002) 39:418–424.[Abstract/Free Full Text]
  17. Zacharia LC, Jackson EK, Gillespie DG, et al. Catecholamines abrogate antimitogenic effects of 2-hydroxyestradiol on human aortic vascular smooth muscle cells. Arterioscler Thromb Vasc Biol (2001) 21:1745–1750.[Abstract/Free Full Text]
  18. Weinshilboum RM, Raymond FA. Inheritance of low erythrocyte catechol-O-methyltransferase activity in man. Am J Hum Genet (1977) 29:125–135.[Web of Science][Medline]
  19. Zubieta JK, Heitzeg MM, Smith YR. COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor. Science (2003) 299:1240–1243.[Abstract/Free Full Text]
  20. Voutilainen S, Tuomainen TP, Korhonen M, et al. Functional COMT Val158Met polymorphism, risk of acute coronary events and serum homocysteine: the kuopio ischaemic heart disease risk factor study. PLoS ONE (2007) 2:e181.[CrossRef]
Received for publication: 20. 8.08
Accepted in revised form: 1. 9.08


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