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.

  • Research Article
  • Published:

Targeting of VEGF-mediated angiogenesis to rat myocardium using ultrasonic destruction of microbubbles

Gene Therapy volume 12, pages 1305–1312 (2005)Cite this article

Abstract

Myocardial angiogenesis mediated by human vascular endothelial growth factor 165 (hVEGF165) cDNA was promoted in rat myocardium using an in vivo-targeted gene delivery system known as ultrasound-targeted microbubble destruction (UTMD). Microbubbles carrying plasmids encoding hVEGF165, or control solutions were infused intravenously during ultrasonic destruction of the microbubbles within the myocardium. Biochemical and histological assessment of gene expression and angiogenesis were performed 5, 10, and 30 days after UTMD. UTMD-treated myocardium contained hVEGF165 protein and mRNA. The myocardium of UTMD-treated animals showed hypercellular foci associated with hVEGF165 expression and endothelial cell markers. Capillary density in UTMD-treated rats increased 18% at 5 days and 33% at 10 days, returning to control levels at 30 days (P<0.0001). Similarly, arteriolar density increased 22% at 5 days, 86% at 10 days, and 31% at 30 days (P<0.0001). Thus, noninvasive delivery of hVEGF165 to rat myocardium by UTMD resulted in significant increases in myocardial capillary and arteriolar density.

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

Similar content being viewed by others

References

  1. Hammond HK, McKirnan MD . Angiogenic gene therapy for heart disease: a review of animal studies and clinical trials. Cardiovasc Res 2001; 49: 561–567.

    Article  CAS  Google Scholar 

  2. Simons M et al. Clinical trials in coronary angiogenesis: issues, problems, consensus: an expert panel summary. Circulation 2000; 102: E73–E86.

    Article  CAS  Google Scholar 

  3. Pecher P, Schumacher BA . Angiogenesis in ischemic human myocardium: clinical results after 3 years. Ann Thorac Surg 2000; 69: 1414–1419.

    Article  CAS  Google Scholar 

  4. Simons M, Ware JA . Therapeutic angiogenesis in cardiovascular disease. Nat Rev Drug Discov 2003; 2: 863–871.

    Article  CAS  Google Scholar 

  5. Rosengart TK et al. Six-month assessment of a Phase I trial of angiogenic gene therapy for the treatment of coronary artery disease using direct intramyocardial administration of an adenovirus vector expressing the VEGF121 cDNA. Ann Surg 1999; 230: 466–472.

    Article  CAS  Google Scholar 

  6. Udelson JE 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 

  7. Henry TD et al. The VIVA trial: vascular endothelial growth factor in ischemia for vascular angiogenesis. Circulation 2003; 107: 1359–1365.

    Article  CAS  Google Scholar 

  8. Simons M et al. Pharmacological treatment of coronary artery disease with recombinant fibroblast growth factor-2: double-blind, randomized, controlled clinical trial. Circulation 2002; 105: 788–793.

    Article  CAS  Google Scholar 

  9. Laham RJ 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 

  10. Ruel M et al. Long-term effects of surgical angiogenic therapy with fibroblast growth factor 2 protein. J Thorac Cardiovasc Surg 2002; 124: 28–34.

    Article  CAS  Google Scholar 

  11. Lederman RJ et al. Therapeutic angiogenesis with recombinant fibroblast growth factor-2 for intermittent claudication (the TRAFFIC study): a randomised trial. Lancet 2002; 359: 2053–2058.

    Article  CAS  Google Scholar 

  12. Grines CL et al. Angiogenic gene therapy (AGENT) trial in patients with stable angina pectoris. Circulation 2002; 105: 1291–1297.

    Article  CAS  Google Scholar 

  13. Losordo DW et al. Phase 1/2 placebo-controlled, double-blind, dose-escalating trial of myocardial vascular endothelial growth factor 2 gene transfer by catheter delivery in patients with chronic myocardial ischemia. Circulation 2002; 105: 2012–2018.

    Article  CAS  Google Scholar 

  14. Hedman M et al. Safety and feasibility of catheter-based local intracoronary vascular endothelial growth factor gene transfer in the prevention of postangioplasty and in-stent restenosis and in the treatment of chronic myocardial ischemia: phase II results of the Kuopio Angiogenesis Trial (KAT). Circulation 2003; 107: 2677–2683.

    Article  CAS  Google Scholar 

  15. Shohet RV et al. Echocardiographic destruction of albumin microbubbles directs gene delivery to the myocardium. Circulation 2000; 101: 2554–2556.

    Article  CAS  Google Scholar 

  16. Chen SY et al. Optimization of ultrasound parameters for cardiac gene delivery of adenoviral or plasmid deoxyribonucleic acid by ultrasound-targeted microbubble destruction. J Am Coll Cardiol 2003; 42: 301–308.

    Article  CAS  Google Scholar 

  17. Bekeredjian R et al. Ultrasound targeted microbubble destruction can repeatedly direct highly specific plasmid expression to the heart. Circulation 2003; 108: 1022–1026.

    Article  Google Scholar 

  18. Dor Y et al. Conditional switching of VEGF provides new insights into adult neovascularization and pro-angiogenic therapy. EMBO J 2002; 21: 1939–1947.

    Article  CAS  Google Scholar 

  19. D'Amore PA . Capillary growth: a two-cell system. Semin Cancer Biol 1992; 3: 49–56.

    CAS  PubMed  Google Scholar 

  20. Carmeliet P, Collen D . Genetic analysis of blood vessel formation. Role of endothelial versus smooth muscle cells. Trends Cardiovasc Med 1997; 7: 271–281.

    Article  CAS  Google Scholar 

  21. Grosskreutz CL et al. Vascular endothelial growth factor-induced migration of vascular smooth muscle cells in vitro. Microvasc Res 1999; 58: 128–136.

    Article  CAS  Google Scholar 

  22. Carmeliet P . Mechanisms of angiogenesis and arteriogenesis. Nat Med 2000; 6: 389–395.

    Article  CAS  Google Scholar 

  23. Song J, Ming QI, Kaul S, Price RJ . Stimulation of arteriogenesis in skeletal muscle by Microbubbles destruction with ultrasound. Circulation 2002; 106: 1550–1555.

    Article  Google Scholar 

  24. Greenleaf WJ et al. Artificial cavitation nuclei significantly enhance acoustically induced cell transfection. Ultrasound Med Biol 1998; 24: 587–595.

    Article  CAS  Google Scholar 

  25. Miller DL, Gies RA . The interaction of ultrasonic heating and cavitation in vascular bioeffects on mouse intestine. Ultrasound Med Biol 1998; 24: 123–128.

    Article  CAS  Google Scholar 

  26. Wu J, Ross JP, Chiu JF . Reparable sonoporation generated by microstreaming. J Acoust Soc Am 2002; 111: 1460–1464.

    Article  Google Scholar 

  27. Kondo T, Misik V, Riesz P . Effect of gas-containing microspheres and echo contrast agents on free radical formation by ultrasound. Free Radic Biol Med 1998; 25: 605–612.

    Article  CAS  Google Scholar 

  28. Skyba DM et al. Direct in vivo visualization of intravascular destruction of microbubbles by ultrasound and its local effects on tissue. Circulation 1998; 98: 290–293.

    Article  CAS  Google Scholar 

  29. Price RJ, Skyba DM, Kaul S, Skalak TC . Delivery of colloidal particles and red blood cells to tissue through microvessel ruptures created by targeted microbubble destruction with ultrasound. Circulation 1998; 98: 1264–1267.

    Article  CAS  Google Scholar 

  30. Croll SD et al. VEGF-mediated inflammation precedes angiogenesis in adult brain. Exp Neurol 2004; 187: 388–402.

    Article  CAS  Google Scholar 

  31. Mor F, Quintana FJ, Cohen IR . Angiogenesis-inflammation cross-talk: vascular endothelial growth factor is secreted by activated T cells and induces Th1 polarization. J Immunol 2004; 172: 4618–4623.

    Article  CAS  Google Scholar 

  32. Chavakis T et al. Regulation of neovascularization by human neutrophil peptides (alpha-defensins): a link between inflammation and angiogenesis. FASEB J 2004; epub ahead of print.

  33. Chen SY et al. Bioeffects of myocardial contrast microbubble destruction by echocardiography. Echocardiography 2002; 19: 495–500.

    Article  CAS  Google Scholar 

  34. Bekeredjian R et al. Effects of ultrasound targeted microbubble destruction on cardiac gene expression. J Ultrasound Med Biol 2004; 30: 539–543.

    Article  Google Scholar 

  35. Hershey JC et al. Revascularization in the rabbit hindlimb: dissociation between capillary sprouting and arteriogenesis. Cardiovasc Res 2001; 49: 618–625.

    Article  CAS  Google Scholar 

  36. Helisch A, Schaper W . Arteriogenesis: the development and growth of collateral arteries. Microcirculation 2003; 10: 83–97.

    Article  Google Scholar 

  37. Ware JA, Simons M . Angiogenesis in ischemic heart disease. Nat Med 1997; 3: 158–164.

    Article  CAS  Google Scholar 

  38. Losordo DW, Dimmeler S . Therapeutic angiogenesis and vasculogenesis for ischemic disease. Part I. Angiogenic cytokines. Circulation 2004; 109: 2487–2491.

    Article  Google Scholar 

  39. Moulton KS et al. Inhibition of plaque neovascularization reduces macrophage accumulation and progression of advanced atherosclerosis. Proc Natl Acad Sci USA 2003; 100: 4736–4741.

    Article  CAS  Google Scholar 

  40. Belgore F et al. Localisation of members of the vascular endothelial growth factor (VEGF) family and their receptors in human atherosclerotic arteries. J Clin Pathol 2004; 57: 266–272.

    Article  CAS  Google Scholar 

  41. Khurana R et al. Angiogenesis-dependent and independent phases of intimal hyperplasia. Circulation 2004; 110: 2436–2443.

    Article  Google Scholar 

  42. Templeton NS et al. Improved DNA: liposome complexes for increased systemic delivery and gene expression. Nat Biotechnol 1997; 15: 647–652.

    Article  CAS  Google Scholar 

  43. Maniatis T, Fritsch EF, Sambrook J . Extraction and Purification of plasmid DNA. In: Sambrook J (ed). Molecular Cloning Manual. Cold Spring Harbor Press: Cold Spring Harbor, NY, 1989, pp 1.38–1.39.

    Google Scholar 

Download references

Acknowledgements

This work was supported by the American Heart Association (Texas Affiliate) 0265186Y (Frenkel), National Institutes of Health K24 HL03890 (Grayburn), American Heart Association (National) 0150586N (Shohet).

Author information

Author notes

  1. G Korpanty and S Chen: These two authors contributed equally to this work

Authors and Affiliations

  1. Division of Cardiology, University of Texas Southwestern Medical School, Dallas, TX, USA

    G Korpanty, S Chen, R V Shohet, P A Frenkel & P A Grayburn

  2. Baylor University Medical Center, Baylor Heart and Vascular Institute, Dallas, TX, USA

    S Chen & P A Grayburn

  3. Baylor University Medical Center, Institute of Metabolic Disease, Dallas, TX, USA

    J Ding & B Yang

  4. Veterans Affairs Medical Center, Dallas, TX, USA

    P A Frenkel

Authors
  1. G Korpanty
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R V Shohet
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. B Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. P A Frenkel
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. P A Grayburn
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Korpanty, G., Chen, S., Shohet, R. et al. Targeting of VEGF-mediated angiogenesis to rat myocardium using ultrasonic destruction of microbubbles. Gene Ther 12, 1305–1312 (2005). https://doi.org/10.1038/sj.gt.3302532

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3302532

Keywords

This article is cited by

Search

Advanced search

Quick links