Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Intramyocardial transplantation of fibroblasts expressing vascular endothelial growth factor attenuates cardiac dysfunction

Gene Therapy volume 17, pages 305–314 (2010)Cite this article

Abstract

In this study, we analyzed whether transplantation of cardiac fibroblasts (CFs) expressing vascular endothelial growth factor (VEGF) mitigates cardiac dysfunction after myocardial infarction (MI) in rats. First, we observed that the transgene expression lasts longer (45 vs 7 days) when fibroblasts are used as vectors compared with myoblasts. In a preventive protocol, induction of cardiac neovascularization accompanied by reduction in myocardial scar area was observed when cell transplantation was performed 1 week before ischemia/reperfusion and the animals analyzed 3 weeks later. Finally, the therapeutic efficacy of this approach was tested injecting cells in a fibrin biopolymer, to increase cardiac retention, 24 h post-MI. After 4 weeks, an increase in neovascularization and a decrease in myocardial collagen were observed only in rats that received cells expressing VEGF. Basal indirect or direct hemodynamic measurements showed no differences among the groups whereas under pharmacological stress, only the group that received cells expressing VEGF showed a significant reduction in end-diastolic pressure and improvement in stroke volume and cardiac work. These results indicate that transplantation of CFs expressing VEGF using fibrin biopolymer induces neovascularization and attenuates left ventricle fibrosis and cardiac dysfunction in ischemic heart.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. Huang C, Ding W, Li L, Zhao D . Differences in the aging-associated trends of the monophasic action potential duration and effective refractory period of the right and left atria of the rat. Circ J 2006; 70: 352–357.

    Article  Google Scholar 

  2. Miyahara Y, Nagaya N, Kataoka M, Yanagawa B, Tanaka K, Hao H et al. Monolayered mesenchymal stem cells repair scarred myocardium after MI. Nat Med 2006; 12: 459–465.

    Article  CAS  Google Scholar 

  3. Pachori AS, Melo LG, Zhang L, Solomon SD, Dzau VJ . Chronic recurrent myocardial ischemic injury is significantly attenuated by pre-emptive adenoassociated virus heme oxygenase-1 gene delivery. J Am Coll Cardiol 2006; 47: 635–643.

    Article  CAS  Google Scholar 

  4. Frangogiannis NG, Entman ML . Chemokines in myocardial ischemia. Trends Cardiovasc Med 2005; 15: 163–169.

    Article  CAS  Google Scholar 

  5. Udelson JE, Dilsizian V, Laham RJ, Chronos N, Vansant J, Blais M et al. Therapeutic angiogenesis with recombinant fibroblast growth factor-2 improves stress and rest myocardial perfusion abnormalities in patients with severe symptomatic chronic coronary artery disease. Circulation 2000; 102: 1605–1610.

    Article  CAS  Google Scholar 

  6. Laham RJ, Sellke FW, Edelman ER, Pearlman JD, Ware JA, Brown DL et al. Local perivascular delivery of basic fibroblast growth factor in patients undergoing coronary bypass surgery: results of a phase I randomized, double-blind, placebo-controlled trial. Circulation 1999; 100: 1865–1871.

    Article  CAS  Google Scholar 

  7. Simons M . Integrative signaling in angiogenesis. Mol Cell Biochem 2004; 264: 99–102.

    Article  CAS  Google Scholar 

  8. Grines CL, Watkins MW, Helmer G, Penny W, Brinker J, Marmur JD et al. Angiogenic Gene Therapy (AGENT) trial in patients with stable angina pectoris. Circulation 2002; 105: 1291–1297.

    Article  CAS  Google Scholar 

  9. Vale PR, Losordo DW, Milliken CE, McDonald MC, Gravelin LM, Curry CM et al. Randomized, single blind, placebo controlled pilot study of catheter-based myocardial gene transfer for therapeutic angiogenesis using left ventricle electromechanical mapping in patients with chronic myocardial ischemia. Circulation 2001; 103: 2138–2143.

    Article  CAS  Google Scholar 

  10. Ylä-Herttuala S, Rissanen TT, Vajanto I, Hartikainen J . Vascular endothelial growth factors: biology and current status of clinical applications in cardiovascular medicine. J Am Coll Cardiol 2007; 10: 1015–1026.

    Article  Google Scholar 

  11. Pettersson A, Nagy JA, Brown LF, Sundberg C, Morgan E, Jungles S et al. Heterogeneity of the angiogenic response induced in different normal adult tissues by vascular permeability factor/vascular endothelial growth factor. Lab Invest 2000; 80: 99–115.

    Article  CAS  Google Scholar 

  12. Lee RJ, Springer ML, Blanco-Bose WE, Shaw R, Ursell PC, Blau HM . VEGF gene delivery to myocardium: deleterious effects of unregulated expression. Circulation 2000; 102: 898–901.

    Article  CAS  Google Scholar 

  13. Koh GY, Kim SJ, Klug MG, Park K, Soonpaa MH, Field LJ . Targeted expression of transforming growth factor-beta 1 in intracardiac grafts promotes vascular endothelial cell DNA synthesis. J Clin Invest 1995; 95: 114–121.

    Article  CAS  Google Scholar 

  14. Suzuki K, Murtuza B, Smolenski RT, Sammut IA, Suzuki N, Kaneda Y et al. Cell transplantation for the treatment of acute MI using vascular endothelial growth factor-expressing skeletal myoblasts. Circulation 2001; 104: 1207–1212.

    Article  Google Scholar 

  15. Santini MP, Tsao L, Monassier L, Theodoropoulos C, Carter J, Lara-Pezzi E et al. Enhancing repair of the mammalian heart. Circ Res 2007; 12: 1732–1740.

    Article  Google Scholar 

  16. Wickham TJ . Targeting adenovirus. Gene Therapy 2000; 7: 110–114.

    Article  CAS  Google Scholar 

  17. Freedman SB, Isner JM . Therapeutic angiogenesis for coronary artery disease. Ann Intern Med 2002; 136: 54–71.

    Article  Google Scholar 

  18. Udelson JE, Dilsizian V, Laham RJ, Chronos N, Vansant J, Blais M et al. Therapeutic angiogenesis with recombinant fibroblast growth factor-2 improves stress and rest myocardial perfusion abnormalities in patients with severe symptomatic chronic coronary artery disease. Circulation 2000; 102: 1605–1610.

    Article  CAS  Google Scholar 

  19. Koh GY, Kim SJ, Klug MG, Park K, Soonpaa MH, Field LJ . Targeted expression of transforming growth factor-beta 1 in intracardiac grafts promotes vascular endothelial cell DNA synthesis. J Clin Invest 1995; 95: 114–121.

    Article  CAS  Google Scholar 

  20. Penn MS, Francis GS, Ellis SG, Young JB, McCarthy PM, Topol EJ . Autologous cell therapy for the treatment of damaged myocardium. Prog Cardiovasc Dis 2002; 45: 21–32.

    Article  Google Scholar 

  21. Anversa P, Leri A, Rota M, Hosoda T, Bearzi C, Urbanek K et al. Concise review: stem cells, myocardial regeneration, and methodological artifacts. Stem Cells 2007; 25: 589–601.

    Article  CAS  Google Scholar 

  22. Becker C, Lacchini S, Muotri AR, da Silva GJ, Castelli JB, Vassallo PF et al. Skeletal muscle cells expressing VEGF induce capillary formation and reduce cardiac injury in rats. Int J Cardiol 2006; 113: 348–354.

    Article  Google Scholar 

  23. Christman KL, Vardanian AJ, Fang Q, Sievers RE, Fok HH, Lee RJ . Injectable fibrin scaffold improves cell transplant survival, reduces infarct expansion, and induces neovasculature formation in ischemic myocardium. J Am Coll Cardiol 2004; 44: 654–660.

    Article  CAS  Google Scholar 

  24. Nakamuta JS, Danoviz ME, Marques FL, dos Santos L, Becker C, Gonçalves GA et al. Cell therapy attenuates cardiac dysfunction post myocardial infarction: effect of timing, routes of injection and a fibrin scaffold. PLoS One 2009; 4: e6005.

    Article  Google Scholar 

  25. Halene S, Wang L, Cooper RM, Bockstoce DC, Robbins PB, Kohn DB . Improved expression in hematopoietic and lymphoid cells in mice after transplantation of bone marrow transduced with a modified retroviral vector. Blood 1999; 94: 3349–3357.

    CAS  PubMed  Google Scholar 

  26. Lee RJ, Springer ML, Blanco-Bose WE, Shaw R, Ursell PC, Blau HM . VEGF gene delivery to myocardium: deleterious effects of unregulated expression. Circulation 2000; 102: 898–901.

    Article  CAS  Google Scholar 

  27. Askari A, Unzek S, Goldman CK, Ellis SG, Thomas JD, DiCorleto PE et al. Cellular, but not direct, adenoviral delivery of vascular endothelial growth factor results in improved left ventricle function and neovascularization in dilated ischemic cardiomyopathy. J Am Coll Cardiol 2004; 43: 1908–1914.

    Article  CAS  Google Scholar 

  28. Ozawa CR, Banfi A, Glazer NL, Thurston G, Springer ML, Kraft PE et al. Microenvironmental VEGF concentration, not total dose, determines a threshold between normal and aberrant angiogenesis. J Clin Invest 2004; 113: 516–527.

    Article  CAS  Google Scholar 

  29. Ngan ES, Lee KY, Yeung WS, Ngan HY, Ng EH, Ho PC . Endocrine gland derived vascular endothelial growth factor is expressed in human periimplantation endometrium, but not in endometrial carcinoma. Endocrinology 2006; 147: 88–95.

    Article  CAS  Google Scholar 

  30. Suzuki K, Murtuza B, Smolenski RT, Sammut IA, Suzuki N, Kaneda Y et al. Cell transplantation for the treatment of acute myocardial infarction using vascular endothelial growth factor expressing skeletal myoblasts. Circulation 2001; 104: 1207–1212.

    Article  Google Scholar 

  31. Anand IS, Liu D, Chugh SS, Prahash AJ, Gupta S, John R et al. Isolated myocyte contractile function is normal in postinfarct remodeled rat heart with systolic dysfunction. Circulation 1997; 96: 3974–3984.

    Article  CAS  Google Scholar 

  32. Fletcher PJ, Pfeffer JM, Pfeffer MA, Braunwald E . Left ventricular diastolic pressure-volume relations in rats with healed myocardial infarction—Effects on systolic function. Circ Res 1981; 49: 618–626.

    Article  CAS  Google Scholar 

  33. Pfeffer MA, Pfeffer JM, Fishbein MC, Fletcher PJ, Spadaro J, Kloner RA et al. Myocardial infarct size and ventricular function in rats. Circ Res 1979; 44: 503–512.

    Article  CAS  Google Scholar 

  34. Kumar R, Hood Jr WB, Joison J, Norman JC, Abelmann WH . Experimental myocardial infarction II. Acute depression and subsequent recovery of left ventricular function: serial measurements in intact conscious dogs. J Clin Invest 1970; 49: 55–62.

    Article  CAS  Google Scholar 

  35. Hood Jr WB . Experimental myocardial infarction. Recovery of left ventricular function in the healing phase. Contribution of increased fiber shortening in noninfarcted myocardium. Am Heart J 1970; 79: 531–538.

    Article  Google Scholar 

  36. Bugge-Asperheim B, Kiil F . Cardiac response to increased aortic pressure. Changes in output and left ventricular pressure pattern at various levels of inotropy. Scand J Clin Lab Invest 1969; 24: 345–360.

    Article  CAS  Google Scholar 

  37. Riazi AM, Lee H, Hsu C, Van Arsdell G . CSX/Nkx2.5 modulates differentiation of skeletal myoblasts and promotes differentiation into neuronal cells in vitro. J Biol Chem 2005; 280: 10716–10720.

    Article  CAS  Google Scholar 

  38. Retuerto MA, Beckmann JT, Carbray J, Patejunas G, Sarateanu S, Kane BJ et al. Angiogenic pretreatment to enhance myocardial function after cellular cardiomyoplasty with skeletal myoblasts. J Thorac Cardiovasc Surg 2007; 133: 478–484.

    Article  Google Scholar 

  39. Ye L, Haider HK, Jiang S, Tan RS, Ge R, Law PK et al. Improved angiogenic response in pig heart following ischaemic injury using human skeletal myoblast simultaneously expressing VEGF165 and angiopoietin-1. Eur J Heart Fail 2007; 9: 15–22.

    Article  CAS  Google Scholar 

  40. Crabos M, Roth M, Hahn AW, Erne P . Characterization of angiotensin II receptors in cultured adult rat cardiac fibroblasts-Coupling to signaling systems and gene expression. J. Clin Invest 1994; 93: 2372–2378.

    Article  CAS  Google Scholar 

  41. Nozawa E, Kanashiro RM, Murad N, Carvalho AC, Cravo SL, Campos O et al. Performance of two-dimensional Doppler echocardiography for the assessment of infarct size and left ventricular function in rats. Braz J Med Biol Res 2006; 39: 687–695.

    Article  CAS  Google Scholar 

  42. Dos Santos L, Santos AA, Gonçalves GA, Krieger JE, Tucci PJ . Bone marrow cell therapy prevents infarct expansion and improves border zone remodeling after coronary occlusion in rats. Int J Cardiol 2009 [e-pub ahead of print 2 July 2009; PMID: 19577315].

Download references

Acknowledgements

This study was funded by grants from public Brazilian Agencies Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP #01/00090), Ministerio da Ciencia e Tecnologia/Conselho Nacional de Desenvolvimento Cientifico e Tecnologico/Ministério da Saude/Departamento Ciencia e Tecnologia (MCT/CNPq/MS/DECIT #552324/20005-1 and 10120104096700). JSN, CB, and GAG were recipients of fellowships from FAPESP (04/06784-4, 03/02671-8 and 03/02672-4, respectively).

Author information

Authors and Affiliations

  1. Department of Medicine, Heart Institute (InCor), University of Sao Paulo Med Sch, Sao Paulo, Brazil

    G A Gonçalves, P F Vassallo, L dos Santos, I T Schettert, J S Nakamuta, C Becker & J E Krieger

  2. Department of Physiology, Cardiac Physiology and Physiopathology Laboratory, UNIFESP, Sao Paulo, Brazil

    P J F Tucci

Authors
  1. G A Gonçalves
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P F Vassallo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L dos Santos
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. I T Schettert
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J S Nakamuta
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C Becker
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. P J F Tucci
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J E Krieger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J E Krieger.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gonçalves, G., Vassallo, P., dos Santos, L. et al. Intramyocardial transplantation of fibroblasts expressing vascular endothelial growth factor attenuates cardiac dysfunction. Gene Ther 17, 305–314 (2010). https://doi.org/10.1038/gt.2009.146

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gt.2009.146

Keywords

This article is cited by

Search

Advanced search

Quick links