Antihypertensive therapy in preeclampsia is not modulated by VEGF polymorphisms

Abstract

Introduction

Vascular endothelial growth factor (VEGF) is relevant for healthy pregnancy, and abnormalities in VEGF functions have been associated with hypertensive disorders of pregnancy. Our group recently demonstrated that VEGF genetic polymorphisms affect the susceptibility to preeclampsia (PE).

Objective

Therefore, in this study our aim is to examine whether VEGF polymorphisms affect the antihypertensive responses in women with PE.

Methods

We studied 113 white PE women who were stratified according to blood pressure levels after antihypertensive treatment (46 responsive, R group and 67 non-responsive, NR group). We then compared the frequencies of two VEGF genetic polymorphisms (C-2578A and G-634C) between R and NR groups.

Results

We found no significant differences in genotype or allele distributions between R and NR groups (P > 0.05). In addition, no difference was observed in overall distribution of haplotypes (P > 0.05).

Conclusion

Our data suggest that VEGF polymorphisms do not affect responsiveness to the antihypertensive therapy in PE.

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References

  1. 1.

    Ahmad S, Ahmed A (2004) Elevated placental soluble vascular endothelial growth factor receptor-1 inhibits angiogenesis in preeclampsia. Circ Res 95:884–891

    Article  CAS  PubMed  Google Scholar 

  2. 2.

    Anonymous (2000) Report of the national high blood pressure education program working group on high blood pressure in pregnancy. Am J Obstet Gynecol 183:S1–S22

    Article  Google Scholar 

  3. 3.

    Awata T, Inoue K, Kurihara S et al (2002) A common polymorphism in the 5′-untranslated region of the VEGF gene is associated with diabetic retinopathy in type 2 diabetes. Diabetes 51:1635–1639

    Article  CAS  PubMed  Google Scholar 

  4. 4.

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

    Article  CAS  PubMed  Google Scholar 

  5. 5.

    Crawford DC, Nickerson DA (2005) Definition and clinical importance of haplotypes. Annu Rev Med 56:303–320

    Article  CAS  PubMed  Google Scholar 

  6. 6.

    de Vasconcelos D, Izidoro-Toledo TC, Sandrim VC et al (2009) Aldosterone synthase gene polymorphism is not associated with gestational hypertension or preeclampsia. Clin Chim Acta 400:139–141

    Article  PubMed  Google Scholar 

  7. 7.

    Demir R, Kayisli UA, Cayli S et al (2006) Sequential steps during vasculogenesis and angiogenesis in the very early human placenta. Placenta 27:535–539

    Article  CAS  PubMed  Google Scholar 

  8. 8.

    Demir R, Kayisli UA, Seval Y et al (2004) Sequential expression of VEGF and its receptors in human placental villi during very early pregnancy: differences between placental vasculogenesis and angiogenesis. Placenta 25:560–572

    Article  CAS  PubMed  Google Scholar 

  9. 9.

    Demir R, Seval Y, Huppertz B (2007) Vasculogenesis and angiogenesis in the early human placenta. Acta Histochem 109:257–265

    Article  CAS  PubMed  Google Scholar 

  10. 10.

    Esser S, Wolburg K, Wolburg H et al (1998) Vascular endothelial growth factor induces endothelial fenestrations in vitro. J Cell Biol 140:947–959

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. 11.

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

    Article  CAS  PubMed  Google Scholar 

  12. 12.

    Girnita DM, Webber SA, Ferrell R et al (2006) Disparate distribution of 16 candidate single nucleotide polymorphisms among racial and ethnic groups of pediatric heart transplant patients. Transplantation 82:1774–1780

    Article  CAS  PubMed  Google Scholar 

  13. 13.

    He H, Venema VJ, Gu X et al (1999) Vascular endothelial growth factor signals endothelial cell production of nitric oxide and prostacyclin through flk-1/KDR activation of c-Src. J Biol Chem 274:25130–25135

    Article  CAS  PubMed  Google Scholar 

  14. 14.

    He Y, Smith SK, Day KA et al (1999) Alternative splicing of vascular endothelial growth factor (VEGF)-R1 (FLT-1) pre-mRNA is important for the regulation of VEGF activity. Mol Endocrinol 13:537–545

    Article  CAS  PubMed  Google Scholar 

  15. 15.

    Jacobs EJ, Feigelson HS, Bain EB et al (2006) Polymorphisms in the vascular endothelial growth factor gene and breast cancer in the Cancer Prevention Study II cohort. Breast Cancer Res 8:R22

    Article  PubMed Central  PubMed  Google Scholar 

  16. 16.

    Johnson GC, Esposito L, Barratt BJ et al (2001) Haplotype tagging for the identification of common disease genes. Nat Genet 29:233–237

    Article  CAS  PubMed  Google Scholar 

  17. 17.

    Kendall RL, Thomas KA (1993) Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc Natl Acad Sci USA 90:10705–10709

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. 18.

    Kendall RL, Wang G, Thomas KA (1996) Identification of a natural soluble form of the vascular endothelial growth factor receptor, FLT-1, and its heterodimerization with KDR. Biochem Biophys Res Commun 226:324–328

    Article  CAS  PubMed  Google Scholar 

  19. 19.

    Kroll J, Waltenberger J (1998) VEGF-A induces expression of eNOS and iNOS in endothelial cells via VEGF receptor-2 (KDR). Biochem Biophys Res Commun 252:743–746

    Article  CAS  PubMed  Google Scholar 

  20. 20.

    Lambrechts D, Storkebaum E, Morimoto M et al (2003) VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death. Nat Genet 34:383–394

    Article  CAS  PubMed  Google Scholar 

  21. 21.

    Maynard SE, Min JY, Merchan J et al (2003) Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest 111:649–658

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. 22.

    Podymow T, August P (2008) Update on the use of antihypertensive drugs in pregnancy. Hypertension 51:960–969

    Article  CAS  PubMed  Google Scholar 

  23. 23.

    Prior SJ, Hagberg JM, Paton CM et al (2006) DNA sequence variation in the promoter region of the VEGF gene impacts VEGF gene expression and maximal oxygen consumption. Am J Physiol Heart Circ Physiol 290:H1848–H1855

    Article  CAS  PubMed  Google Scholar 

  24. 24.

    Roberts JM, Gammill HS (2005) Preeclampsia: recent insights. Hypertension 46:1243–1249

    Article  CAS  PubMed  Google Scholar 

  25. 25.

    Sandrim VC, Coelho EB, Nobre F et al (2006) Susceptible and protective eNOS haplotypes in hypertensive black and white subjects. Atherosclerosis 186:428–432

    Article  CAS  PubMed  Google Scholar 

  26. 26.

    Sandrim VC, de Syllos RWC, Lisboa HR et al (2006) Endothelial nitric oxide synthase haplotypes affect the susceptibility to hypertension in patients with type 2 diabetes mellitus. Atherosclerosis 189:241–246

    Article  CAS  PubMed  Google Scholar 

  27. 27.

    Sandrim VC, Palei AC, Cavalli RC et al (2009) Vascular endothelial growth factor genotypes and haplotypes are associated with pre-eclampsia but not with gestational hypertension. Mol Hum Reprod 15:115–120

    Article  CAS  PubMed  Google Scholar 

  28. 28.

    Sandrim VC, Palei AC, Luizon MR et al (2010) eNOS haplotypes affect the responsiveness to antihypertensive therapy in preeclampsia but not in gestational hypertension. Pharmacogenomics J 10(1):40–45

    Article  CAS  PubMed  Google Scholar 

  29. 29.

    Sandrim VC, Yugar-Toledo JC, Desta Z et al (2006) Endothelial nitric oxide synthase haplotypes are related to blood pressure elevation, but not to resistance to antihypertensive drug therapy. J Hypertens 24:2393–2397

    Article  CAS  PubMed  Google Scholar 

  30. 30.

    Schneider BP, Radovich M, Sledge GW et al (2007) Association of polymorphisms of angiogenesis genes with breast cancer. Breast Cancer Res Treat 20:20

    Google Scholar 

  31. 31.

    Shahbazi M, Fryer AA, Pravica V et al (2002) Vascular endothelial growth factor gene polymorphisms are associated with acute renal allograft rejection. J Am Soc Nephrol 13:260–264

    CAS  PubMed  Google Scholar 

  32. 32.

    Shen BQ, Lee DY, Zioncheck TF (1999) Vascular endothelial growth factor governs endothelial nitric-oxide synthase expression via a KDR/Flk-1 receptor and a protein kinase C signaling pathway. J Biol Chem 274:33057–33063

    Article  CAS  PubMed  Google Scholar 

  33. 33.

    Shibuya M (2001) Structure and function of VEGF/VEGF-receptor system involved in angiogenesis. Cell Struct Funct 26:25–35

    Article  CAS  PubMed  Google Scholar 

  34. 34.

    Sibai BM (2008) Intergenerational Factors. A Missing Link for Preeclampsia, Fetal Growth Restriction, and Cardiovascular Disease? Hypertension 7:7

    Google Scholar 

  35. 35.

    Sibai BM, Barton JR (2007) Expectant management of severe preeclampsia remote from term: patient selection, treatment, and delivery indications. Am J Obstet Gynecol 196:514

    Article  PubMed  Google Scholar 

  36. 36.

    Smith GC, Crossley JA, Aitken DA et al (2007) Circulating angiogenic factors in early pregnancy and the risk of preeclampsia, intrauterine growth restriction, spontaneous preterm birth, and stillbirth. Obstet Gynecol 109:1316–1324

    Article  CAS  PubMed  Google Scholar 

  37. 37.

    Venkatesha S, Toporsian M, Lam C et al (2006) Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med 12:642–649

    Article  CAS  PubMed  Google Scholar 

  38. 38.

    Walker JJ (2000) Pre-eclampsia. Lancet 356:1260–1265

    Article  CAS  PubMed  Google Scholar 

  39. 39.

    Zachary I (2001) Signaling mechanisms mediating vascular protective actions of vascular endothelial growth factor. Am J Physiol Cell Physiol 280:C1375–C1386

    CAS  PubMed  Google Scholar 

  40. 40.

    Zhou Y, McMaster M, Woo K et al (2002) Vascular endothelial growth factor ligands and receptors that regulate human cytotrophoblast survival are dysregulated in severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome. Am J Pathol 160:1405–1423

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was funded by the ‘Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)’ and ‘Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)’.

Conflict of interest

All authors declare the absence of conflict.

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Correspondence to Valeria C. Sandrim.

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Sandrim, V.C., Palei, A.C.T., Eleuterio, N. et al. Antihypertensive therapy in preeclampsia is not modulated by VEGF polymorphisms. Arch Gynecol Obstet 291, 799–803 (2015). https://doi.org/10.1007/s00404-014-3475-2

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Keywords

  • Preeclampsia
  • VEGF
  • Polymorphism