J Korean Med Sci.  2007 Feb;22(1):94-98. 10.3346/jkms.2007.22.1.94.

The Levels of Circulating Vascular Endothelial Growth Factor and Soluble Flt-1 in Pregnancies Complicated by Preeclampsia

• Lee ES
• Oh MJ
• Jung JW
• Lim JE
• Seol HJ
• Lee KJ
• Kim HJ

• KMID: 1713238
• DOI: http://doi.org/10.3346/jkms.2007.22.1.94

Abstract

To evaluate the role of vascular endothelial growth factor (VEGF) in the pathogenesis of preeclampsia, we measured total VEGF, free VEGF and soluble Flt-1 (sFlt-1) concentrations and determined their relationships. Maternal serum samples were collected from 20 patients with preeclampsia and 20 normotensive women with uncomplicated pregnancies matched with the patients with preeclampsia for gestational age and parity. The serum concentrations of total VEGF (2.39+/-0.75 vs. 0.28+/-0.14) and sFlt-1 (934.5+/-235.5 vs. 298.0+/-161.2) were significantly increased in the patients with preeclampsia compared to the women with uncomplicated pregnancies. However the serum concentration of free VEGF (21.5+/-6.3 vs. 134.0+/-16.3) was lower in patients with preeclampsia. There was a positive correlation between the serum concentrations of total VEGF and sFlt-1 with systolic and diastolic blood pressure, respectively. There was a negative correlation between the serum concentration of free VEGF and systolic and diastolic blood pressure. There was a strong negative correlation between free VEGF and sFlt-1 concentrations. In conclusion, we found VEGF and sFlt-1 were related to the pathogenesis of preeclampsia. Although reduced concentrations of free VEGF might interfere with endothelial cell function and survival, further studies are required to clarify its specific role in the pathogenesis of preeclampsia.

Keyword

Pre-eclampsia; Vascular Endothelial Growth Factor; sFlt-1; Vasular Endothelial Growth Factor Receptor-1

MeSH Terms

Vascular Endothelial Growth Factor Receptor-1/*blood
Vascular Endothelial Growth Factor A/*blood/physiology
Pregnancy
Pre-Eclampsia/*blood/etiology
Humans
Female
Adult

Figure

• 

  Fig. 1 Distribution of Total VEGF levels (A), sFlt-1 levels (B), and Free VEGF levels in serum (C). P, preeclampsia; U, unaffected pregnancy. Difference were significant: (A) p<0.001, (B) p<0.0001, (C) p<0.001. Values are given as mean±SD. Statistical significance was assessed using Mann-Whitney U test.

• 

  Fig. 2 (A) There was a positive correlation between the serum concentration of total VEGF and systolic pressure and diastolic pressure. (B) Positive correlation between the serum concentration of sFlt-1 and systolic pressure and diastolic pressure. (C) Negative correlation between serum concentration of free VEGF and systolic pressure and diastolic pressure. (D) Negative correlation between serum concentration of free VEGF and serum concentration of sFlt-1. Difference were siginificant: (A) p<0.0001, (B) p<0.001, (C) p<0.0001, (D) p<0.0001. Values are given as mean±SD. Statistical significance was assessed using the ANOVA and linear regression analyses.

Reference

1. Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, Schisterman EF, Thadhani R, Sachs BP, Epstein FH, Sibai BM, Sukhatme VP, Karumanchi SA. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med. 2004. 350:672–683.

2. Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, Libermann TA, Morgan JP, Sellke FW, Stillman IE, Epstein FH, Sukhatme VP, Karumanchi SA. 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.

3. Lee GS, Lee JK, Han WS, Lee Y, Kim SJ, Rha JG, Kim SP, Namkoong SE. The expression of vascular endothelial growth factor, platelet-derived growth factor and intercellular adhesion molecule in severe preeclamptic placenta. Korean J Obstet Gynecol. 2003. 46:606–611.

4. Luttun A, Carmeliet P. Soluble VEGF receptor Flt-1: the elusive preeclampsia factor discovered? J Clin Invest. 2003. 111:600–602.

5. Jelkmann W. Pitfalls in the measurement of circulating vascular endothelial growth factor. Clin Chem. 2001. 47:617–623.

6. Sugimoto H, Hamano Y, Charytan D, Cosrove D, Kieran M, Sudhakar A, Kalluri R. 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.

7. Ferrara N, Houck K, Jakeman L, Leung DW. Molecular and biological properties of the vascular endothelial growth factor family of proteins. Endocr Rev. 1992. 13:18–32.

8. Chaiworapongsa T, Romero R, Espinoza J, Bujold E, Mee Kim Y, Gonclaves LF, Gomez R, Edwin S. Evidence supporting a role for blockade of the vascular endothelial growth factor system in the pathophsiology of preeclampsia. Am J Obstet Gynecol. 2004. 190:1541–1550.

9. Kupferminc MJ, Daniel Y, Englender T, Baram A, Many A, Jaffa AJ, Gull I, Lessing JB. Vascular endothelial growth factor is increased in patients with preeclampsia. Am J Reprod Immunol. 1997. 38:302–306.

10. Cho YK, Min HJ, Park KH, Choi H, Kim BR, Lee HK. Serum concentration of vascular endothelial growth factor in preeclamptic women. Korean J Obstet Gynecol. 2000. 43:1967–1971.

11. Lee KJ, Oh MJ, Kim HJ, Kim SH, Lee JK, Hur JY, Saw HS, Park YK. Correlation of serum vascular endothelial growth factor and matrix metalloproteinase-2 in patients complicated with preeclampsia and normotensive pregnant women. Korean J Obstet Gynecol. 2005. 48:29–35.

12. Polliotti BM, Fry AG, Saller DN, Mooney RA, Cox C, Miller RK. Second-trimester maternal serum placental growth factor and vascular endothelial growth factor for predicting severe, early onset preeclampsia. Obstet Gynecol. 2003. 101:1266–1274.

13. Koga K, Osuga Y, Yoshino O, Hirota Y, Ruimeng X, Hirata T, Takeda S, Yano T, Tsutsumi O, Taketani Y. Elevated serum soluble vascular endothelial growth factor receptor 1 (sVEGFR-1) levels in women with preeclampsia. J Clin Endocrinol Metab. 2003. 88:2348–2351.

14. Brockelsby JC, Hayman R, Ahmed A, Warren A, Johnson I, Baker P. VEGF via VEGF receptor-1 (Flt-1) mimics preeclamptic plasma in inhibiting uterine blood vessel relaxation in pregnancy: implications in the pathogenesis of preeclampsia. Lab Invest. 1999. 79:1101–1111.

15. Levine RJ, Ewell MG, Hauth JC, Curet LB, Catalano PM, Morris CD, Choudhary G, Sibai BM. Should the definition of preeclampsia include a rise in diastolic blood pressure of >/=15 mm Hg to a level <90 mm Hg in association with proteinuria? Am J Obstet Gynecol. 2000. 183:787–792.

16. Oh MJ, Shin JC, Popek EJ. Vascular endothelial growth factor expression in patients complicated preeclampsia. Korean J Obstet Gynecol. 2001. 44:1877–1882.

17. Lyall F, Greer IA, Boswell F, Fleming R. Suppression of serum vascular endothelial growth factor immunoreactivity in normal pregnancy and in preeclampsia. Br J Obstet Gynecol. 1997. 104:223–228.

18. Reuvekamp A, Velsing-Aarts FV, Poulina IEJ, Capello JJ, Duits AJ. Selective deficit of angiogenic growth factor characterizes pregnancies complicated by preeclampsia. Br J Obstet Gynecol. 1999. 106:1019–1022.

19. Baker PN, Krasnow J, Roberts JM, Yeo KT. Elevated serum levels of vascular endothelial growth factor in patients with preeclampsia. Obstet Gynecol. 1995. 86:815–821.

20. Sharkey AM, Cooper JC, Balmforth JR, Mclaren J, Clark DE, Charnock-Jones DS, Morris NH, Smith SK. Maternal plasma levels of vascular endothelial growth factor in normotensive pregnancies and pregnancies complicated by preeclampsia. Eur J Clin Invest. 1996. 26:1182–1185.

21. Brockelsby JC, Anthony FW, Johnson IR, Wheeler T, Baker PN. Increased serum vascular endothelial growth factor concentrations in pre-eclampsia. Hypertens Pregnancy. 1998. 17:283–290.

22. Shibuya M. Role of VEGF-flt receptor system in normal and tumor angiogenesis. Adv Cancer Res. 1995. 67:281–316.

23. Brockelsby JC, Anthony FW, Johnson IR, Baker PN. The effects of vascular endothelial growth factor on endothelial cells: A potential role in preeclampsia. Am J Obstet Gynecol. 2000. 182:176–183.

24. Cho YK, Lee HK. The effect of VEGF on endothelial cells in pathogenesis of preeclampsia. Korean J Obstet Gynecol. 2002. 45:1354–1359.

25. Hood JD, Meininger CJ, Ziche M, Granger HJ. VEGF upregulates ecNOS message, protein, and NO production in human endothelial cells. Am J Physiol. 1998. 274:H1054–H1058.

26. Ashworth JR, Warren AY, Johnson IR, Baker PN. Plasma from preeclamptic women and functional change in myometrial resistance arteries. Br J Obstet Gynecol. 1998. 105:459–461.

27. Anthony FW, Evans PW, Wheeler T, Wood PJ. Variation in detection of VEGF in maternal serum by immunoassay and the possible influence of binding proteins. Ann Clin Biochem. 1997. 34:276–280.

28. Bhattacharjee G, Asplin IR, Wu SM, Gawdi G, Pizzo SV. The conformation-dependent interaction of α₂-macroglobulin with vascular endothelial growth factor. J Biol Chem. 2000. 275:26806–26811.

29. Jung SH, Oh MJ, Suk YS, Lim JE, Seol HJ, Kim HJ. The effect of α₂-macroglobulin on VEGF-induced endothelin-1 upregulation in human umbilical vein endothelial cells. Placenta. 2006. 27:A50.