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The relationship between circulating endothelin-1, soluble fms-like tyrosine kinase-1 and soluble endoglin in preeclampsia

Journal of Human Hypertension volume 26, pages 236–241 (2012)Cite this article

Abstract

Placental overproduction of anti-angiogenic soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) has a key role in the development of preeclampsia (PE). Circulating endothelin-1 (ET-1) levels are also elevated in PE. In this study, we investigated the correlation between ET-1 and sFlt-1, placental growth factor (PlGF), sEng levels during uncomplicated normotensive pregnancy and PE. A total of 218 pregnant primigravid women were enrolled: 110 with PE and 108 uncomplicated normotensive pregnancies. PE was defined as new onset of elevated blood pressure (BP) >140/90 mm Hg and ⩾2+ proteinuria on two occasions after 20 weeks of gestation in previously normotensive pregnant women. Circulating ET-1, sFlt-1, sEng and PlGF levels were estimated using enzyme immunoassays, and correlation between variables was ascertained. Women with PE showed higher levels of sFlt-1 (41.5±15.7 vs 6.15±3.4 ng ml–1, P<0.001), sEng (84.9±38.8 vs 13.2±6.3 ng ml–1, P<0.001), ET-1 (1.52±0.55 vs 0.88±0.35 pg ml–1, P<0.001) and sFlt-1:PlGF ratio (591.1±468.4 vs 18.3±2.1, P<0.001); and lower levels of PlGF (96.3±47.2 vs 497.6±328.2pg ml–1, P<0.001). BP levels showed an independent relationship with sFlt-1:PlGF ratio in normotensive pregnant women and with sFlt-1:PlGF ratio and ET-1 in PE. sFlt-1 and sFlt-1:PlGF ratio correlated with proteinuria. ET-1 correlated significantly with sFlt-1, sEng and sFlt-1:PlGF ratio in PE. Our results show an association between elevation of sFlt-1 and sEng and ET-1 in the maternal circulation in PE, and strengthen the possibility that ET-1 may be a mediator in genesis of PE syndrome secondary to anti-angiogenic factors released by the placenta.

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References

  1. Noris M, Perico N, Remuzzi G . Mechanisms of disease: pre-eclampsia. Nat Clin Pract Nephrol 2005; 1: 98–114; quiz 120.

    Article  CAS  Google Scholar 

  2. Sibai B, Dekker G, Kupferminc M . Pre-eclampsia. Lancet 2005; 365: 785–799.

    Article  Google Scholar 

  3. Gilbert JS, Ryan MJ, LaMarca BB, Sedeek M, Murphy SR, Granger JP . Pathophysiology of hypertension during preeclampsia: linking placental ischemia with endothelial dysfunction. Am J Physiol Heart Circ Physiol 2008; 294: H541–H550.

    Article  CAS  Google Scholar 

  4. Granger JP, Alexander BT, Llinas MT, Bennett WA, Khalil RA . Pathophysiology of hypertension during preeclampsia linking placental ischemia with endothelial dysfunction. Hypertension 2001; 38: 718–722.

    Article  CAS  Google Scholar 

  5. Gu Y, Lewis DF, Wang Y . Placental productions and expressions of soluble endoglin, soluble fms-like tyrosine kinase receptor-1, and placental growth factor in normal and preeclamptic pregnancies. J Clin Endocrinol Metab 2008; 93: 260–266.

    Article  CAS  Google Scholar 

  6. Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S 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.

    Article  CAS  Google Scholar 

  7. Venkatesha S, Toporsian M, Lam C, Hanai J, Mammoto T, Kim YM et al. Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med 2006; 12: 642–649.

    Article  CAS  Google Scholar 

  8. Levine RJ, Lam C, Qian C, Yu KF, Maynard SE, Sachs BP et al. Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. N Engl J Med 2006; 355: 992–1005.

    Article  CAS  Google Scholar 

  9. Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 2004; 350: 672–683.

    Article  CAS  Google Scholar 

  10. Livingston JC, Chin R, Haddad B, McKinney ET, Ahokas R, Sibai BM . Reductions of vascular endothelial growth factor and placental growth factor concentrations in severe preeclampsia. Am J Obstet Gynecol 2000; 183: 1554–1557.

    Article  CAS  Google Scholar 

  11. Tsatsaris V, Goffin F, Munaut C, Brichant JF, Pignon MR, Noel A et al. Overexpression of the soluble vascular endothelial growth factor receptor in preeclamptic patients: pathophysiological consequences. J Clin Endocrinol Metab 2003; 88: 5555–5563.

    Article  CAS  Google Scholar 

  12. Aggarwal PK, Jain V, Srinivasan R, Jha V . Maternal EDN1 G5665 T polymorphism influences circulating endothelin-1 levels and plays a role in determination of preeclampsia phenotype. J Hypertens 2009; 27: 2044–2050.

    Article  CAS  Google Scholar 

  13. Barden AE, Herbison CE, Beilin LJ, Michael CA, Walters BN, Van Bockxmeer FM . Association between the endothelin-1 gene Lys198Asn polymorphism blood pressure and plasma endothelin-1 levels in normal and pre-eclamptic pregnancy. J Hypertens 2001; 19: 1775–1782.

    Article  CAS  Google Scholar 

  14. Clark BA, Halvorson L, Sachs B, Epstein FH . Plasma endothelin levels in preeclampsia: elevation and correlation with uric acid levels and renal impairment. Am J Obstet Gynecol 1992; 166: 962–968.

    Article  CAS  Google Scholar 

  15. Greer IA, Leask R, Hodson BA, Dawes J, Kilpatrick DC, Liston WA . Endothelin, elastase, and endothelial dysfunction in pre-eclampsia. Lancet 1991; 337: 558.

    Article  CAS  Google Scholar 

  16. Taylor RN, Varma M, Teng NN, Roberts JM . Women with preeclampsia have higher plasma endothelin levels than women with normal pregnancies. J Clin Endocrinol Metab 1990; 71: 1675–1677.

    Article  CAS  Google Scholar 

  17. Karumanchi SA, Epstein FH . Placental ischemia and soluble fms-like tyrosine kinase 1: cause or consequence of preeclampsia? Kidney Int 2007; 71: 959–961.

    Article  CAS  Google Scholar 

  18. Sladek SM, Magness RR, Conrad KP . Nitric oxide and pregnancy. Am J Physiol 1997; 272: R441–R463.

    CAS  PubMed  Google Scholar 

  19. Williams DJ, Vallance PJ, Neild GH, Spencer JA, Imms FJ . Nitric oxide-mediated vasodilation in human pregnancy. Am J Physiol 1997; 272: H748–H752.

    CAS  PubMed  Google Scholar 

  20. Alexander BT, Rinewalt AN, Cockrell KL, Massey MB, Bennett WA, Granger JP . Endothelin type a receptor blockade attenuates the hypertension in response to chronic reductions in uterine perfusion pressure. Hypertension 2001; 37: 485–489.

    Article  CAS  Google Scholar 

  21. Roberts L, LaMarca BB, Fournier L, Bain J, Cockrell K, Granger JP . Enhanced endothelin synthesis by endothelial cells exposed to sera from pregnant rats with decreased uterine perfusion. Hypertension 2006; 47: 615–618.

    Article  CAS  Google Scholar 

  22. Gilbert JS, Babcock SA, Granger JP . Hypertension produced by reduced uterine perfusion in pregnant rats is associated with increased soluble fms-like tyrosine kinase-1 expression. Hypertension 2007; 50: 1142–1147.

    Article  CAS  Google Scholar 

  23. Gilbert JS, Gilbert SA, Arany M, Granger JP . Hypertension produced by placental ischemia in pregnant rats is associated with increased soluble endoglin expression. Hypertension 2009; 53: 399–403.

    Article  CAS  Google Scholar 

  24. Collino F, Bussolati B, Gerbaudo E, Marozio L, Pelissetto S, Benedetto C et al. Preeclamptic sera induce nephrin shedding from podocytes through endothelin-1 release by endothelial glomerular cells. Am J Physiol Renal Physiol 2008; 294: F1185–F1194.

    Article  CAS  Google Scholar 

  25. Sugimoto H, Hamano Y, Charytan D, Cosgrove D, Kieran M, Sudhakar A et al. Neutralization of circulating vascular endothelial growth factor (VEGF) by anti-VEGF antibodies and soluble VEGF receptor 1 (sFlt-1) induces proteinuria. J Biol Chem 2003; 278: 12605–12608.

    Article  CAS  Google Scholar 

  26. Murphy SR, LaMarca BB, Cockrell K, Granger JP . Role of endothelin in mediating soluble fms-like tyrosine kinase 1-induced hypertension in pregnant rats. Hypertension 2010; 55: 394–398.

    Article  CAS  Google Scholar 

  27. Bridges JP, Gilbert JS, Colson D, Gilbert SA, Dukes MP, Ryan MJ et al. Oxidative stress contributes to soluble fms-like tyrosine kinase-1 induced vascular dysfunction in pregnant rats. Am J Hypertens 2009; 22: 564–568.

    Article  CAS  Google Scholar 

  28. Sandrim VC, Palei AC, Cavalli RC, Araujo FM, Ramos ES, Duarte G et al. Vascular endothelial growth factor genotypes and haplotypes are associated with pre-eclampsia but not with gestational hypertension. Mol Hum Reprod 2009; 15: 115–120.

    Article  CAS  Google Scholar 

  29. Aggarwal PK, Jain V, Jha V . Endothelial nitric oxide synthase, angiotensin-converting enzyme and angiotensinogen gene polymorphisms in hypertensive disorders of pregnancy. Hypertens Res 2010; 33: 473–477.

    Article  CAS  Google Scholar 

  30. Wang CN, Chang SD, Peng HH, Lee YS, Chang YL, Cheng PJ et al. Change in amniotic fluid levels of multiple anti-angiogenic proteins before development of preeclampsia and intrauterine growth restriction. J Clin Endocrinol Metab 2010; 95: 1431–1441.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by a grant from the Department of Biotechnology, Ministry of Science and Technology, Government of India to VJ. PKA received a fellowship from the Indian Council of Medical Research.

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  1. Department of Nephrology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

    P K Aggarwal, N Chandel & V Jha

  2. Department Obstetrics and Gynaecology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

    V Jain

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  1. P K Aggarwal
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Correspondence to V Jha.

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Aggarwal, P., Chandel, N., Jain, V. et al. The relationship between circulating endothelin-1, soluble fms-like tyrosine kinase-1 and soluble endoglin in preeclampsia. J Hum Hypertens 26, 236–241 (2012). https://doi.org/10.1038/jhh.2011.29

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