Skip to main content

Advertisement

SpringerLink
Log in

Polymorphisms in VEGFA gene affect the antihypertensive responses to enalapril

  • Pharmacogenetics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that affects blood pressure by promoting vasodilation mediated by nitric oxide. Angiotensin-converting enzyme inhibitors (ACEi) up-regulate the VEGF expression; thus, genetic polymorphisms in the VEGFA gene could affect the antihypertensive responses to these drugs.

Methods

Hypertensive patients (n = 102) were prospectively treated only with the ACEi enalapril for 60 days. We compared the effect of VEGFA polymorphisms on changes in blood pressure after enalapril treatment. In addition, multiple linear regression analysis was carried out to assess the effect of covariates on blood pressure. Genotypes for g.-2578C>A (rs699947), g.-1154G>A (rs1570360), and g.-634G>C (rs2010963) VEGFA polymorphisms were determined, and haplotype frequencies were estimated.

Results

Individuals carrying the CA and AA genotypes for the g.-2578C>A polymorphism and the AGG haplotype showed more intense decrease in blood pressure in response to enalapril 20 mg/day. A multiple linear regression analysis showed that the AA genotype for the g.-2578C>A polymorphism and the AGG haplotype are associated with more intense decrease in blood pressure in response to enalapril 20 mg/day, while the CC genotype for the g.-2578C>A polymorphism and the CGG haplotype are associated with the opposite effect.

Conclusions

These findings suggest that polymorphisms in VEGFA gene may affect the antihypertensive responses to enalapril.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ (2003) The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA J Am Med Assoc 289(19):2560–2572

    Article  CAS  Google Scholar 

  2. von Lueder TG, Krum H (2013) RAAS inhibitors and cardiovascular protection in large scale trials. Cardiovasc Drugs Ther 27(2):171–179

    Article  CAS  Google Scholar 

  3. Mentz RJ, Bakris GL, Waeber B, McMurray JJ, Gheorghiade M, Ruilope LM, Maggioni AP, Swedberg K, Pina IL, Fiuzat M, O’Connor CM, Zannad F, Pitt B (2013) The past, present and future of renin-angiotensin aldosterone system inhibition. Int J Cardiol 167(5):1677–1687

    Article  PubMed Central  PubMed  Google Scholar 

  4. Ebrahimian TG, Tamarat R, Clergue M, Duriez M, Levy BI, Silvestre JS (2005) Dual effect of angiotensin-converting enzyme inhibition on angiogenesis in type 1 diabetic mice. Arterioscler Thromb Vasc Biol 25(1):65–70

    CAS  PubMed  Google Scholar 

  5. Ferroni P, Della-Morte D, Palmirotta R, Rundek T, Guadagni F, Roselli M (2012) Angiogenesis and hypertension: the dual role of anti-hypertensive and anti-angiogenic therapies. Curr Vasc Pharmacol 10(4):479–493

    Article  CAS  PubMed  Google Scholar 

  6. Li P, Kondo T, Numaguchi Y, Kobayashi K, Aoki M, Inoue N, Okumura K, Murohara T (2008) Role of bradykinin, nitric oxide, and angiotensin II type 2 receptor in imidapril-induced angiogenesis. Hypertension 51(2):252–258

    Article  CAS  PubMed  Google Scholar 

  7. Silvestre JS, Kamsu-Kom N, Clergue M, Duriez M, Levy BI (2002) Very-low-dose combination of the angiotensin-converting enzyme inhibitor perindopril and the diuretic indapamide induces an early and sustained increase in neovascularization in rat ischemic legs. J Pharmacol Exp Ther 303(3):1038–1043

    Article  CAS  PubMed  Google Scholar 

  8. Toblli JE, Cao G, DeRosa G, Di Gennaro F, Forcada P (2004) Angiotensin-converting enzyme inhibition and angiogenesis in myocardium of obese Zucker rats. Am J Hypertens 17(2):172–180

    Article  CAS  PubMed  Google Scholar 

  9. Yazawa H, Miyachi M, Furukawa M, Takahashi K, Takatsu M, Tsuboi K, Ohtake M, Murase T, Hattori T, Kato Y, Murohara T, Nagata K (2011) Angiotensin-converting enzyme inhibition promotes coronary angiogenesis in the failing heart of Dahl salt-sensitive hypertensive rats. J Card Fail 17(12):1041–1050

    Article  CAS  PubMed  Google Scholar 

  10. Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9(6):669–676

    Article  CAS  PubMed  Google Scholar 

  11. Eppler SM, Combs DL, Henry TD, Lopez JJ, Ellis SG, Yi JH, Annex BH, McCluskey ER, Zioncheck TF (2002) A target-mediated model to describe the pharmacokinetics and hemodynamic effects of recombinant human vascular endothelial growth factor in humans. Clin Pharmacol Ther 72(1):20–32

    Article  CAS  PubMed  Google Scholar 

  12. Facemire CS, Nixon AB, Griffiths R, Hurwitz H, Coffman TM (2009) Vascular endothelial growth factor receptor 2 controls blood pressure by regulating nitric oxide synthase expression. Hypertension 54(3):652–658

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Henry TD, Annex BH, McKendall GR, Azrin MA, Lopez JJ, Giordano FJ, Shah PK, Willerson JT, Benza RL, Berman DS, Gibson CM, Bajamonde A, Rundle AC, Fine J, McCluskey ER (2003) The VIVA trial: vascular endothelial growth factor in ischemia for vascular angiogenesis. Circulation 107(10):1359–1365

    Article  CAS  PubMed  Google Scholar 

  14. Horowitz JR, Rivard A, van der Zee R, Hariawala M, Sheriff DD, Esakof DD, Chaudhry GM, Symes JF, Isner JM (1997) Vascular endothelial growth factor/vascular permeability factor produces nitric oxide-dependent hypotension. Evidence for a maintenance role in quiescent adult endothelium. Arterioscler Thromb Vasc Biol 17(11):2793–2800

    Article  CAS  PubMed  Google Scholar 

  15. Ku DD, Zaleski JK, Liu S, Brock TA (1993) Vascular endothelial growth factor induces EDRF-dependent relaxation in coronary arteries. Am J Physiol 265(2 Pt 2):H586–H592

    CAS  PubMed  Google Scholar 

  16. Liu MH, Jin HK, Floten HS, Yang Q, Yim AP, Furnary A, Zioncheck TF, Bunting S, He GW (2001) Vascular endothelial growth factor-mediated endothelium-dependent relaxation is blunted in spontaneously hypertensive rats. J Pharmacol Exp Ther 296(2):473–477

    CAS  PubMed  Google Scholar 

  17. Messadi E, Aloui Z, Belaidi E, Vincent MP, Couture-Lepetit E, Waeckel L, Decorps J, Bouby N, Gasmi A, Karoui H, Ovize M, Alhenc-Gelas F, Richer C (2014) Cardioprotective effect of VEGF and venom VEGF-like protein in acute myocardial ischemia in mice: effect on mitochondrial function. J Cardiovasc Pharmacol 63(3):274–281

    Article  CAS  PubMed  Google Scholar 

  18. Thijs AM, van Herpen CM, Sweep FC, Geurts-Moespot A, Smits P, van der Graaf WT, Rongen GA (2013) Role of endogenous vascular endothelial growth factor in endothelium-dependent vasodilation in humans. Hypertension 61(5):1060–1065

    Article  CAS  PubMed  Google Scholar 

  19. Vyzantiadis T, Karagiannis A, Douma S, Harsoulis P, Vyzantiadis A, Zamboulis C (2006) Vascular endothelial growth factor and nitric oxide serum levels in arterial hypertension. Clin Exp Hypertens 28(7):603–609

    Article  CAS  PubMed  Google Scholar 

  20. Erdos EG, Tan F, Skidgel RA (2010) Angiotensin I-converting enzyme inhibitors are allosteric enhancers of kinin B1 and B2 receptor function. Hypertension 55(2):214–220

    Article  PubMed Central  PubMed  Google Scholar 

  21. Thuringer D, Maulon L, Frelin C (2002) Rapid transactivation of the vascular endothelial growth factor receptor KDR/Flk-1 by the bradykinin B2 receptor contributes to endothelial nitric-oxide synthase activation in cardiac capillary endothelial cells. J Biol Chem 277(3):2028–2032

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  23. Belo VA, Souza-Costa DC, Luizon MR, Izidoro-Toledo TC, Lanna CM, Pinheiro LC, Tanus-Santos JE (2011) Vascular endothelial growth factor haplotypes associated with childhood obesity. DNA Cell Biol 30(9):709–714

    Article  CAS  PubMed  Google Scholar 

  24. Goncalves FM, Martins-Oliveira A, Speciali JG, Izidoro-Toledo TC, Luizon MR, Dach F, Tanus-Santos JE (2010) Vascular endothelial growth factor genetic polymorphisms and haplotypes in women with migraine. DNA Cell Biol 29(7):357–362

    Article  CAS  PubMed  Google Scholar 

  25. Lacchini R, Luizon MR, Gasparini S, Ferreira-Sae MC, Schreiber R, Nadruz W Jr, Tanus-Santos JE (2014) Effect of genetic polymorphisms of vascular endothelial growth factor on left ventricular hypertrophy in patients with systemic hypertension. Am J Cardiol 113(3):491–496

    Article  CAS  PubMed  Google Scholar 

  26. Lacchini R, Muniz JJ, Nobre YT, Cologna AJ, Martins AC, Tanus-Santos JE (2013) VEGF genetic polymorphisms affect the responsiveness to sildenafil in clinical and postoperative erectile dysfunction. Pharmacogenomics J 13(5):437–442. doi: 10.1038/tpj.2012.39

  27. Lambrechts D, Storkebaum E, Morimoto M, Del-Favero J, Desmet F, Marklund SL, Wyns S, Thijs V, Andersson J, van Marion I, Al-Chalabi A, Bornes S, Musson R, Hansen V, Beckman L, Adolfsson R, Pall HS, Prats H, Vermeire S, Rutgeerts P, Katayama S, Awata T, Leigh N, Lang-Lazdunski L, Dewerchin M, Shaw C, Moons L, Vlietinck R, Morrison KE, Robberecht W, Van Broeckhoven C, Collen D, Andersen PM, Carmeliet P (2003) VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death. Nat Genet 34(4):383–394

    Article  CAS  PubMed  Google Scholar 

  28. Sandrim VC, Luizon MR, Izidoro-Toledo TC, Coelho EB, Moreno H Jr, Tanus-Santos JE (2013) Functional VEGF haplotypes affect the susceptibility to hypertension. J Hum Hypertens 27(1):31–37

    Article  CAS  PubMed  Google Scholar 

  29. Shahbazi M, Fryer AA, Pravica V, Brogan IJ, Ramsay HM, Hutchinson IV, Harden PN (2002) Vascular endothelial growth factor gene polymorphisms are associated with acute renal allograft rejection. J Am Soc Nephrol 13(1):260–264

    CAS  PubMed  Google Scholar 

  30. Steffensen KD, Waldstrom M, Brandslund I, Jakobsen A (2010) The relationship of VEGF polymorphisms with serum VEGF levels and progression-free survival in patients with epithelial ovarian cancer. Gynecol Oncol 117(1):109–116

    Article  CAS  PubMed  Google Scholar 

  31. Banyasz I, Szabo S, Bokodi G, Vannay A, Vasarhelyi B, Szabo A, Tulassay T, Rigo J Jr (2006) Genetic polymorphisms of vascular endothelial growth factor in severe pre-eclampsia. Mol Hum Reprod 12(4):233–236

    Article  CAS  PubMed  Google Scholar 

  32. Sandrim VC, Palei AC, Cavalli RC, Araujo FM, Ramos ES, Duarte G, Tanus-Santos JE (2009) Vascular endothelial growth factor genotypes and haplotypes are associated with pre-eclampsia but not with gestational hypertension. Mol Hum Reprod 15(2):115–120

    Article  CAS  PubMed  Google Scholar 

  33. Esteghamati A, Noshad S, Jarrah S, Mousavizadeh M, Khoee SH, Nakhjavani M (2013) Long-term effects of addition of mineralocorticoid receptor antagonist to angiotensin II receptor blocker in patients with diabetic nephropathy: a randomized clinical trial. Nephrol Dial Transplant 28(11):2823–2833

    Article  CAS  PubMed  Google Scholar 

  34. Maharaj B, van der Byl K (1993) A comparative study of isradipine SRO and enalapril in black patients with mild-to-moderate hypertension. Am J Hypertens 6(3 Pt 2):80S–81S

    CAS  PubMed  Google Scholar 

  35. Hansson L, Zanchetti A (1994) The Hypertension Optimal Treatment (HOT) study—patient characteristics: randomization, risk profiles, and early blood pressure results. Blood Press 3(5):322–327

    Article  CAS  PubMed  Google Scholar 

  36. Ruf G, Gera S, Luus HG, Trenk D, de la Rey N, Loffler K, Schulz W, Jahnchen E (1994) Pharmacokinetics and pharmacodynamics of ramipril and piretanide administered alone and in combination. Eur J Clin Pharmacol 46(6):545–550

    Article  CAS  PubMed  Google Scholar 

  37. Cholley BP, Shroff SG, Sandelski J, Korcarz C, Balasia BA, Jain S, Berger DS, Murphy MB, Marcus RH, Lang RM (1995) Differential effects of chronic oral antihypertensive therapies on systemic arterial circulation and ventricular energetics in African-American patients. Circulation 91(4):1052–1062

    Article  CAS  PubMed  Google Scholar 

  38. Stephens M, Smith NJ, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68(4):978–989

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Muniz JJ, Izidoro-Toledo TC, Metzger IF, Sandrim VC, Tanus-Santos JE (2009) Interethnic differences in the distribution of clinically relevant vascular endothelial growth factor genetic polymorphisms. DNA Cell Biol 28(11):567–572

    Article  CAS  PubMed  Google Scholar 

  40. Zachary I (2001) Signaling mechanisms mediating vascular protective actions of vascular endothelial growth factor. Am J Physiol Cell Physiol 280(6):C1375–C1386

    CAS  PubMed  Google Scholar 

  41. Prior SJ, Hagberg JM, Paton CM, Douglass LW, Brown MD, McLenithan JC, Roth SM (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(5):H1848–H1855

    Article  CAS  PubMed  Google Scholar 

  42. Kim OJ, Hong SH, Oh SH, Kim TG, Min KT, Oh D, Kim NK (2011) Association between VEGF polymorphisms and homocysteine levels in patients with ischemic stroke and silent brain infarction. Stroke 42(9):2393–2402

    Article  CAS  PubMed  Google Scholar 

  43. Gu JW, Manning RD Jr, Young E, Shparago M, Sartin B, Bailey AP (2009) Vascular endothelial growth factor receptor inhibitor enhances dietary salt-induced hypertension in Sprague–Dawley rats. Am J Physiol Regul Integr Comp Physiol 297(1):R142–R148

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Vormfelde SV, Sehrt D, Bolte D, Pahl S, Tzvetkov M, Brockmoller J (2006) Hydrochlorothiazide efficacy and polymorphisms in ACE, ADD1 and GNB3 in healthy, male volunteers. Eur J Clin Pharmacol 62(3):195–201

    Article  CAS  PubMed  Google Scholar 

  45. Silva PS, Fontana V, Luizon MR, Lacchini R, Silva WA Jr, Biagi C, Tanus-Santos JE (2013) eNOS and BDKRB2 genotypes affect the antihypertensive responses to enalapril. Eur J Clin Pharmacol 69(2):167–177

    Article  CAS  PubMed  Google Scholar 

Download references

Compliance with ethical standards

Acknowledgments

This study was supported by Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) and Fundaçao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP).

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Author information

Authors and Affiliations

  1. Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Av. Bandeirantes, 3900, 14049-900, Ribeirao Preto, SP, Brazil

    G. H. Oliveira-Paula & Jose E. Tanus-Santos

  2. Department of Psychiatric Nursing and Human Sciences, Ribeirao Preto College of Nursing, University of Sao Paulo, Ribeirao Preto, SP, Brazil

    R. Lacchini

  3. Brazilian Biosciences National Laboratory, CNPEM, Campinas, SP, Brazil

    V. Fontana

  4. Department of Pharmacy, Faculty of Pharmacy, Federal University of Juiz de Fora, Governador Valadares, MG, Brazil

    P. S. Silva

  5. Santa Casa de Araçatuba, Araçatuba, SP, Brazil

    C. Biagi

Authors
  1. G. H. Oliveira-Paula
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R. Lacchini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. V. Fontana
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P. S. Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C. Biagi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jose E. Tanus-Santos
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jose E. Tanus-Santos.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Table S1

(DOCX 16 kb)

Table S2

(DOCX 16 kb)

Table S3

(DOCX 15 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Oliveira-Paula, G.H., Lacchini, R., Fontana, V. et al. Polymorphisms in VEGFA gene affect the antihypertensive responses to enalapril. Eur J Clin Pharmacol 71, 949–957 (2015). https://doi.org/10.1007/s00228-015-1872-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-015-1872-5

Keywords

Search

Navigation