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Long-term VEGF-A expression promotes aberrant angiogenesis and fibrosis in skeletal muscle

Gene Therapy volume 18, pages 1166–1172 (2011)Cite this article

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A Corrigendum to this article was published on 09 June 2011

This article has been updated

Abstract

Vascular endothelial growth factor A (VEGF-A) induces strong angiogenesis and it has been widely used in proangiogenic gene therapy studies. However, little is known about long-term effects of VEGF-A expression in skeletal muscle. Here the long- term effects of adeno-associated virus (AAV) encoding human VEGF-A165 (AAV-VEGF-A) gene transfer in normal and ischemic rabbit hindlimb skeletal muscles were studied. AAV-LacZ was used as a control. In one-year follow-up, a remarkable increase in skeletal muscle perfusion compared with AAV-LacZ was observed measured with Doppler and contrast pulse sequence ultrasound. Angiogenesis was also seen in histology as enlarged and sprouting capillaries. In addition to favorable angiogenic effects, aberrant vascular structures with CD31 positive cell layers were seen inside muscle fibers after AAV-VEGF-A gene transfer. Importantly, we found increased amounts of extracellular matrix with a high number of macrophages and fibrosis in AAV-VEGF-A transduced muscles. No changes in skeletal muscle morphology were detected in AAV-LacZ transduced muscles. Our results indicate that local AAV-VEGF-A gene transfer efficiently promotes long-term angiogenesis in large animal model. However, non-regulated expression of VEGF-A causes unfavorable changes in muscle morphology, which suggests the need for regulation of the transgene expression in long-term AAV-mediated VEGF-A gene transfer applications.

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Change history

  • 08 December 2011

    This article has been corrected since Advance Online Publication and a corrigendum is also printed in this issue

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Acknowledgements

This study was supported by grants from Finnish Academy, Finnish Foundation for Cardiovascular Research, Finnish Cultural Foundation, North Savo Regional Fund, Sigrid Juselius Foundation, Emil Aaltonen Foundation, Aarne Koskelo Foundation and Maud Kuistila Foundation. We acknowledge the Technicians in the group of Molecular Medicine and at the Experimental Animal Center at University of Eastern Finland for their expert technical help.

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Authors and Affiliations

  1. Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland

    H Karvinen, E Pasanen, T T Rissanen, P Korpisalo, E Vähäkangas & S Ylä-Herttuala

  2. Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland

    A Jazwa

  3. Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology, Trieste, Italy

    M Giacca

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  1. H Karvinen
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Correspondence to S Ylä-Herttuala.

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Karvinen, H., Pasanen, E., Rissanen, T. et al. Long-term VEGF-A expression promotes aberrant angiogenesis and fibrosis in skeletal muscle. Gene Ther 18, 1166–1172 (2011). https://doi.org/10.1038/gt.2011.66

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