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Soluble VEGFR-1 in pathophysiology of pregnancies complicated by hypertensive disorders: the Indian scenario

Journal of Human Hypertension volume 27, pages 107–114 (2013)Cite this article

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Abstract

An imbalance between angiogenic and anti-angiogenic factors has been hypothesized to have a major role in hypertensive disorders during pregnancy, which account for significant morbidity and mortality for the mother and neonate in India. There is a paucity of information on soluble vascular endothelial growth factor receptor-1 (sVEGFR-1, anti-angiogenic factor) concentrations in different subgroups of pregnancy-induced hypertensive (PIH) disorders particularly in gestational hypertension (GH) and eclampsia during pregnancy. This cross-sectional study was conducted in order to test the above hypothesis and to get more insight into the role of sVEGFR-1 in these disorders. The concentrations of sVEGFR-1 in serum were measured from women with 22–39 weeks of gestation in the control (n=180) and gestationally matched hypertensive (n=360) pregnant mothers by ELISA. These sVEGFR-1 concentrations were found to be significantly elevated in the study groups as the severity of disease increases from GH to eclampsia (24 076 pg ml−1; 42 000 pg ml−1, P=0.0001) as compared with controls (3360 pg ml−1). According to Receiver operating characteristic curve analysis, at ⩽34 weeks, the concentration cutoff, sensitivity, specificity for sVEGFR-1 in differentiating GH, pre-eclampsia and eclampsia were ⩾7619.2 pg ml−1, 75%, 75%; ⩾16 726.6 pg ml−1, 89.1%, 89.1%; ⩾26 222.8 pg ml−1, 91.6%, 91.6%, respectively. The gradual upregulation of sVEGFR-1 concentrations in these groups may be due to its intimate involvement in the etiopathogenesis of severity of various hypertensive disorders by antagonizing effects of VEGF during the placental development. These observations indicate the clinical utility of sVEGFR-1 in differentiating PIH disorders and also will be helpful for the evaluation of increased monitoring system for successful pregnancy.

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References

  1. Roberts JM, Cooper DW . Pathogenesis and genetics of Pre-eclampsia. Lancet 2001; 357: 53.

    Article  CAS  PubMed  Google Scholar 

  2. Chhabra S . Maternal morbidity with caesarean section for non-progress of labour: an analytical study. J Indian Med Assoc 2007; 105 (12): 684–686.

    CAS  PubMed  Google Scholar 

  3. Roberts JM, Lain KY . Recent insight into the pathogenesis of Pre-eclampsia. Placenta 2002; 23: 359–372.

    Article  CAS  PubMed  Google Scholar 

  4. National high blood pressure education program working group on high blood pressure in pregnancy. Report of the National high blood pressure education program working group on high blood pressure in pregnancy. Am J Obst Gyne 2000; 183: s1–s22.

    Article  Google Scholar 

  5. Diagnosis and management of preeclampsia and eclampsia. ACOG Practice Bulletin No. 33. American College of Obstetricians and Gynecologists. Obstet Gynecol 2002; 99: 159–167.

    Google Scholar 

  6. Valensise H, Vasapollo B, Gagliardi G, Novelli GP . Early and late preeclampsia: two different maternal hemodynamic states in the latent phase of the disease. Hypertension 2008; 52: 873–880.

    Article  CAS  PubMed  Google Scholar 

  7. Mbah AK, Alio AP, Marty PJ, Bruder K, Whiteman VE, Salihu HM . Pre- eclampsia in the first pregnancy and subsequent risk of stillbirth in black and white gravidas. Eur J Obstet Gynecol Reprod Biol 2010; 149: 165–169.

    Article  PubMed  Google Scholar 

  8. Hauth JC, Ewell MG, Levine RJ, Esterlitz JR, Sibai B, Curet LB et al. Pregnancy outcomes in healthy nulliparas who developed hypertension. Calcium for Preeclampsia Prevention Study Group. Obstet Gynecol 2000; 95: 24–28.

    CAS  PubMed  Google Scholar 

  9. Hutcheon JA, Lisonkova S, Joseph KS . Epidemiology of pre-eclampsia and the other hypertensive disorders of pregnancy. Best Pract Res Clin Obstet Gynaecol 2011; 25 (4): 391–403.

    Article  PubMed  Google Scholar 

  10. Ebos JM, Bocci G, Man S, Thorpe PE, Hicklin DJ, Zhou D et al. A naturally occurring soluble form of vascular endothelial growth factor receptor-2 detected in mouse and human plasma. Mol Cancer Res 2004; 2: 315–326.

    CAS  PubMed  Google Scholar 

  11. Ferrara N, Gerber HP, LeCouter J . The biology of VEGF and its receptors. Nat Med 2003; 9: 669–676.

    Article  CAS  PubMed  Google Scholar 

  12. Tripathi R, Rath G, Ralhan R, Saxena S, Salhan S . Soluble and membranous Vascular Endothelial Growth Factor Receptor-2 in pregnancies complicated by Pre-eclampsia. Yonsei Med J 2009; 50 (5): 656–666.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Agostini H, Boden K, Unsold A, Martin G, Hansen L, Fiedler U et al. A single local injection of recombinant VEGFR-2 but not of Tie2 inhibits retinal neovascularization in the mouse. Curr Eye Res 2005; 30: 249–257.

    Article  CAS  PubMed  Google Scholar 

  14. Shalaby F, Ho J, Stanford WL, Fischer KD, Schuh AC, Schwartz L et al. A requirement for Flk1 in primitive and definitive hematopoiesis and vasculogenesis. Cell 1997; 89: 981–990.

    Article  CAS  PubMed  Google Scholar 

  15. Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S et al. Excess placental soluble fms-like tyrosine kinase 1(sFlt-1) may contribute to endothelial dysfunction, hypertension and proteinuria in Pre-eclampsia. J Clin Invest 2003; 111: 649–658.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Levine RJ, Lam C, Qian C, Yu KF, Maynard SE, Sachs BP et al. Karumanchi S.A. Soluble endoglin and other circulating anti-angiogenic factors in Pre-eclampsia. N Engl J Med 2006; 355: 992–1005.

    Article  CAS  PubMed  Google Scholar 

  17. Marini M, Vichi D, Toscano A, Zappoli Thyrion GD, Parretti E, Mello G et al. Expression of vascular endothelial growth factor receptor types 1, 2 and 3 in placenta from pregnancies complicated by hypertensive disorders. Reprod Fertil Dev 2007; 9: 641–651.

    Article  Google Scholar 

  18. Chaiworapongsa T, Romero R, Kim YM, Kim GJ, Kim MR, Espinoza J et al. Plasma soluble vascular endothelial growth factor receptor-1 concentration is elevated prior to the clinical diagnosis of pre-eclampsia. J Matern Fetal Neonatal Med 2005; 17: 3–18.

    Article  CAS  PubMed  Google Scholar 

  19. Masuyama H, Segawa T, Sumida Y, Masumoto A, Inoue S, Akahori Y et al. Different profiles of circulating angiogenic factors and adipocytokines between early- and late-onset pre-eclampsia. BJOG 2010; 117: 314–320.

    Article  CAS  PubMed  Google Scholar 

  20. Verlohren S, Herraiz I, Lapaire O, Schlembach D, Moertl M, Zeisler H et al. The sFlt-1/PlGF ratio in different types of hypertensive pregnancy disorders and its prognostic potential in preeclamptic patients. Am J Obstet Gynecol 2011; 206 (1): 58.e1-8.

    PubMed  Google Scholar 

  21. Vaisbuch E, Whitty JE, Hassan SS, Romero R, Kusanovic JP, Cotton DB et al. Circulating angiogenic and antiangiogenic factors in women with Eclampsia. Am J Obstet Gynecol 2011; 204 (2): 152.e1–152.e9.

    Article  Google Scholar 

  22. Huppertz B, Kingdom J, Caniggia I, Desoye G, Black S, Korr H et al. Hypoxia favours necrotic versus apoptotic shedding of placental syncytiotrophoblast into the maternal circulation. Placenta 2003; 24 (2-3): 181–190.

    Article  CAS  PubMed  Google Scholar 

  23. Romero R, Nien JK, Espinoza J, Todem D, Fu W, Chung H et al. A longitudinal study of angiogenic (placental growth factor) and anti-angiogenic (soluble endoglin and soluble vascular endothelial growth factor receptor-1) factors in normal pregnancy and patients destined to develop pre-eclampsiaand deliver a small for gestational age neonate. J Mat Fet Neon Med 2008; 21 (1): 9–23.

    CAS  Google Scholar 

  24. Koga K, Osuga Y, Yoshino O, Hirota Y, Ruimeng X, Hirata T et al Elevated serum soluble vascular endothelial growth factor receptor-1(sVEGFR-1) levels in women with pre-eclampsia. J Clin Endo Metab 2003; 88 (5): 2348–2351.

    Article  CAS  Google Scholar 

  25. Unal C, Robinson D, Johnson E, Chang EY . Second-trimester angiogenic factors as biomarkers for future-onset Pre-eclampsia AJOG 197. Am J Obstet Gynecol 2007; 2: 211.e1–211.e4.

    Article  Google Scholar 

  26. Vuorela P, Helske S, Hornig C, Alitalo K, Weich H, Halmesmaki E . Amniotic fluid-soluble vascular endothelial growth factor receptor-1 in Pre-eclampsia. Obstet Gynecol 2000; 95: 353–357.

    CAS  PubMed  Google Scholar 

  27. Shalaby F, Ho J, Stanford WL, Fischer KD, Schuh AC, Schwartz L et al. A requirement for Flk1 in primitive and definitive hematopoiesis and vasculogenesis. Cell 1997; 89: 981–990.

    Article  CAS  PubMed  Google Scholar 

  28. Robinson CJ, Stringer SE . The splice variants of vascular endothelial growth factor (VEGF) and their receptors. J Cell Sci 2001; 114: 853–865.

    CAS  PubMed  Google Scholar 

  29. Ahmad S, Ahmed A . Elevated placental soluble vascular endothelial growth factor receptor-1 inhibits angiogenesis in preeclampsia. CircRes 2004; 95: 884–891.

    CAS  Google Scholar 

  30. Nevo O, Soleymanlou N, Wu Y, Xu J, Kingdom J, Many A et al. Increased expression of sFlt-1 in in vivo and in vitro models of human placental hypoxia is mediated by HIF-1. Am J Physiol Regul Integr Comp Physiol 2006; 291 (4): R1085–R1093.

    Article  CAS  PubMed  Google Scholar 

  31. Kumazaki K, Nakayama M, Suehara N, Wada Y . Expression of vascular endothelial growth factor, placental growth factor, and their receptors Flt-1 and KDR in human placenta under pathological conditions. Hum Pathol 2002; 33: 1069–1077.

    Article  CAS  PubMed  Google Scholar 

  32. Barleon B, Reusch P, Totzke F, Herzog C, Keck C, Martiny-Barleon G et al. SVEGFR-1 secreted by endothelial cells and monocytes is present in human serum and plasma from healthy donors. Angiogenesis 2001; 4: 143–154.

    Article  CAS  PubMed  Google Scholar 

  33. Matsubara K, Nagamatsu T, Fujii T, Kozuma S, Taketani Y . Lymphokine activated killer cells induced from decidual lymphocytes reduce the angiogenic activity of trophoblasts by enhancing the release of sFlt-1 from trophoblasts: An implication for the pathophysiology of Pre-eclampsia. J Reprod Immunol 2005; 68: 27–37.

    Article  CAS  PubMed  Google Scholar 

  34. Geva E, Ginzinger DG, Zaloudek CJ, Moore DH, Byrne A, Jaffe RB . Human placental vascular development vasculogenic and angiogenic (branching and non-branching) transformation is regulated by VEGF, angiopoietin-1 and angiopoietin-2. J Clin Endocrinol Metab 2002; 87 (9): 4213–4224.

    Article  CAS  PubMed  Google Scholar 

  35. Girardi G, Yarilin D, Thurman JM, Holers VM, Salmon JE . Complement activation induces dysregulation of angiogenic factors and causes fetal rejection and growth restriction. J Exp Med 2006; 203: 2165–2175.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Stepan H, Faber R, Wessel N, Wallukat G, Schultheiss HP, Walther T . Relation between circulating angiotensin II type 1 receptor agonistic autoantibodies and soluble fms-like tyrosine kinase 1 in the pathogenesis of Pre-eclampsia. J Clin Endocrinol Metab 2006; 91: 2424–2427.

    Article  CAS  PubMed  Google Scholar 

  37. Munaut C, Lorquet S, Pequeux C, Blacher S, Berndt S, Frankenne F et al. Hypoxia is responsible for soluble vascular endothelial growth factor receptor-1 (VEGFR-1) but not for soluble endoglin induction in villous trophoblast. Hum Reprod 2008; 23 (6): 1407–1415.

    Article  CAS  PubMed  Google Scholar 

  38. Rahimi N . VEGFR-1 and VEGFR-2: two non-identical twins with a unique physiognomy. Front Biosci 2006; 11: 818–829.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Hunter A, Aitkenhead M, Caldwell C, McCracken G, Wilson D, McClure N . Serum levels of vascular endothelial growth factor in pre-eclamptic and normotensive pregnancy. Hypertension 2000; 36: 965.

    Article  CAS  PubMed  Google Scholar 

  40. Rath G, Tripathi R . VEGF and its soluble receptor VEGFR-2 in hypertensive disorders during pregnancy: the Indian scenario. J Hum Hypertens 2011 ( in press).

  41. Salahuddin S, Young L, Vadnais M, Benjamin P, Sachs S, Karumanchi A et al. Diagnostic utility of soluble fms-like tyrosine kinase 1 and soluble endoglin in hypertensive diseases of pregnancy. Amer J Obst Gynec 2007; 197: 28.e1–28.e6.

    Article  Google Scholar 

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Acknowledgements

This work was supported by a grant of Council of Scientific and Industrial Research (CSIR Project No. 27-0133/04/EMR II), New Delhi, India. Dr Richa Tripathi was the recipient of the Senior Research Fellowship of Indian Council of Medical Research (ICMR), New Delhi, India.

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Authors and Affiliations

  1. Department of Anatomy, Vardhman Mahavir Medical College and Safdarjang Hospital, New Delhi, India

    R Tripathi & G Rath

  2. Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India

    R Ralhan

  3. Institute of Pathology, Safdarjang Hospital, New Delhi, India

    S Saxena

  4. Department of Obstetrics and Gynaecology, Vardhman Mahavir Medical College and Safdarjang Hospital, New Delhi, India

    S Salhan

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  1. R Tripathi
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Correspondence to G Rath.

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Tripathi, R., Ralhan, R., Saxena, S. et al. Soluble VEGFR-1 in pathophysiology of pregnancies complicated by hypertensive disorders: the Indian scenario. J Hum Hypertens 27, 107–114 (2013). https://doi.org/10.1038/jhh.2012.2

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