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.

  • Brief Communication
  • Published:

Adeno-associated virus (AAV)-7 and -8 poorly transduce vascular endothelial cells and are sensitive to proteasomal degradation

Gene Therapy volume 12, pages 1534–1538 (2005)Cite this article

Abstract

Transduction of the vascular endothelium by adeno-associated virus (AAV) vectors would have broad appeal for gene therapy. However, levels of transduction by AAV serotype-2 are low, an observation linked to deficiencies in endothelial cell binding, sequestration of virions in the extracellular matrix and/or virion degradation by the proteasome. Strategies to improve transduction of endothelial cells include AAV-2 capsid targeting using small peptides isolated by phage display or the use of alternate serotypes. Previously, we have shown that AAV serotypes-3 through -6 transduce endothelial cells with poor efficiency. Recently, AAV serotypes-7 and -8 have been shown to mediate efficient transduction of the skeletal muscle and liver, respectively, although their infectivity profile for vascular cells has not been addressed. Here, we show that AAV-7 and -8 also transduce endothelial cells with poor efficiency and the levels of transgene expression are markedly enhanced by inhibition of the proteasome. In both cases proteasome blockade enhances the nuclear translocation of virions. We further show that this is vascular cell-type selective since transduction of smooth muscle cells is not sensitive to proteasome inhibition. Analysis in intact blood vessels corroborated these findings and suggests that proteasome degradation is a common limiting factor for endothelial cell transduction by AAV vectors.

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

Similar content being viewed by others

References

  1. Yla-Herttuala S, Martin J . Cardiovascular gene therapy. Lancet 2000; 355: 213–217.

    Article  CAS  Google Scholar 

  2. 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 ischemai. Phase II results of the Kupoio Angiogenesis Trial (KAT). Circulation 2003; 107: 2677–2683.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  4. Lemarchand P, Jones M, Yamada I, Crystal RG . In vivo gene transfer and expression in normal uninjured blood vessels using replication-deficient recombinant adenovirus vectors. Circ Res 1993; 72: 1132–1138.

    Article  CAS  Google Scholar 

  5. French BA et al. Percutaneous transluminal in vivo gene transfer by recombinant adenovirus in normal procine coronary arteries, atherosclerotic arteries, and two models of coronary restenosis. Circulation 1994; 90: 2402–2413.

    Article  CAS  Google Scholar 

  6. George S et al. Adenovirus-mediated gene transfer of the human TIMP-1 gene inhibits smooth muscle cell migration and neomintimal formation in human saphenous vein. Hum Gene Ther 1998; 9: 867–877.

    Article  CAS  Google Scholar 

  7. Newman KD et al. Adenovirus-mediated gene transfer into normal rabbit arteries results in prolonged vascular cell activation, inflammation, and neointimal hyperplasia. J Clin Invest 1995; 96: 2955–2965.

    Article  CAS  Google Scholar 

  8. Maeda Y et al. Gene transfer into vascular cells using adeno-associated virus (AAV) vectors. Cardiovas Res 1997; 35: 514–521.

    Article  CAS  Google Scholar 

  9. Richter M et al. Adeno-associated virus vector transduction of vascular smooth muscle cells in vivo. Physiol Genomics 2000; 2: 117–127.

    Article  CAS  Google Scholar 

  10. Melo LG et al. Gene therapy strategy for long-term myocardial protection using adeno-associated virus-mediated delivery of heme oxygenase gene. Circulation 2002; 105: 602–607.

    Article  CAS  Google Scholar 

  11. Nicklin S et al. Efficient and selective AAV2-mediated gene transfer directed to human vascular endothelial cells. Mol Ther 2001; 4: 174–181.

    Article  CAS  Google Scholar 

  12. Pajusola K et al. Cell-type-specific characteristics modulate the transduction efficiency of adeno-associated virus type 2 and restrain infection of endothelial cells. J Virol 2002; 76: 11530–11540.

    Article  CAS  Google Scholar 

  13. Yan Z et al. Distinct classes of proteasome-modulating agents cooperatively augment recombinant adeno-associated virus type 2 and type 5 mediated transduction from the apical surfaces of human airway epithelia. Virology 2004; 78: 2863–2874.

    Article  CAS  Google Scholar 

  14. Duan D et al. Endosomal processing limits gene transfer to polarized airway epithelia by adeno-associated virus. J Clin Invest 2000; 105: 1573–1587.

    Article  CAS  Google Scholar 

  15. Wilson SH et al. Activated nuclear factor-kappa B is present in the coronary vasculature in experimental hypercholesterolemia. Atheroscelerosis 2000; 148: 23–30.

    Article  CAS  Google Scholar 

  16. Herrmann J, Gulati R, Napoli C . Oxidative stress-related increase in ubiquitination in early coronary atherosclerosis. FASEB J 2003; 17: 1730–1732.

    Article  CAS  Google Scholar 

  17. Herrmann J, Ciechanover A, Lerman LO, Lerman A . The ubiquitin-proteasome system in cardiovascular diseases – a hypothesis extended. Cardiovasc Res 2004; 61: 11–21.

    Article  CAS  Google Scholar 

  18. Baker AH . Targeting AAV vectors. Mol Ther 2003; 4: 433–434.

    Article  Google Scholar 

  19. White S et al. Gene delivery to vascular tissue in vivo by tropism-modified adeno-associated virus vectors. Circulation 2004; 109: 513–519.

    Article  CAS  Google Scholar 

  20. Work L et al. Development of efficient viral vectors selective for vascular smooth muscle cells. Mol Ther 2004; 9: 198–208.

    Article  CAS  Google Scholar 

  21. Dishart KL et al. Third-generation lentivirus vectors efficiently transduce and phenotypically modify vascular cells: implications for gene therapy. J Mol Cell Cardiol 2003; 35: 739–748.

    Article  CAS  Google Scholar 

  22. Gao G-P et al. Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy. Proc Natl Acad Sci USA 2002; 99: 11854–11859.

    Article  CAS  Google Scholar 

  23. Sarkar R et al. Total correction of hemophilia A mice with canine FVIII using an AAV 8 serotype. Gene Therapy 2004; 103: 1253–1260.

    CAS  Google Scholar 

  24. Louboutin J et al. Gene transfer into skeletal muscle using novel AAV serotypes. J Gen Med, E-pub ahead of print.

  25. Nicol CG et al. Effect of adenovirus serotype 5 fiber and penton modifications on in vivo tropism in rats. Mol Ther 2004; 10: 343–353.

    Article  Google Scholar 

  26. Maher PA . Nuclear translocation of fibroblast growth factor (FGF) receptors in response to FGF-2. J Cell Biol 1996; 134: 529–536.

    Article  CAS  Google Scholar 

  27. Sperinde GV, Nugent MA . Heparan sulfate proteoglycans control intracellular processing of bFGF in vascular smooth muscle cells. Biochemistry 1998; 38: 13153–13164.

    Article  Google Scholar 

Download references

Acknowledgements

We thank Nicola Britton for technical assistance. This work was funded by the Medical Research Council (UK), National Kidney Research Fund (UK) and the Biotechnology and Biomedical Sciences Research Council.

Author information

Authors and Affiliations

  1. Division of Cardiovascular and Medical Sciences, British Heart Foundation, Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK

    L Denby, S A Nicklin & A H Baker

Authors
  1. L Denby
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S A Nicklin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A H Baker
    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

Denby, L., Nicklin, S. & Baker, A. Adeno-associated virus (AAV)-7 and -8 poorly transduce vascular endothelial cells and are sensitive to proteasomal degradation. Gene Ther 12, 1534–1538 (2005). https://doi.org/10.1038/sj.gt.3302564

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3302564

Keywords

This article is cited by

Search

Advanced search

Quick links