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Cardiovascular Research Advance Access first published online on July 22, 2008
This version [Corrected Proof] published online on August 5, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn195
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Therapeutic angiogenesis with placental growth factor improves exercise tolerance of ischaemic rabbit hindlimbs

Petra Korpisalo1,{dagger}, Tuomas T. Rissanen1,{dagger}, Timo Bengtsson1, Timo Liimatainen1, Svetlana Laidinen1, Henna Karvinen1, Johanna E. Markkanen1, Olli H. Gröhn2 and Seppo Ylä-Herttuala1,3,4,*

1 Department of Molecular Medicine, A.I. Virtanen Institute, University of Kuopio, PO Box 1627, FIN-70211 Kuopio, Finland
2 Department of Neurobiology, A.I. Virtanen Institute, University of Kuopio, Kuopio, Finland
3 Department of Medicine, University of Kuopio, Kuopio, Finland
4 Gene Therapy Unit, University of Kuopio, Kuopio, Finland

* Corresponding author. Tel: +358 17 162075; fax: +358 17 163751. E-mail address: seppo.ylaherttuala{at}uku.fi

Aims: We investigated the effects of angiogenic gene therapy with adenoviral placental growth factor131 (AdPlGF) on aerobic capacity and exercise tolerance in a rabbit hindlimb ischaemia model. We also assessed whether strong angiogenic changes such as capillary arterialization and formation of artery-venous shunts compromise oxygen transport to target tissues resulting in suboptimal therapeutic efficacy.

Methods and results: Hindlimb ischaemia was surgically induced in New Zealand White rabbits (n = 20) that a day later received intramuscular (i.m.) AdPlGF or AdLacZ (3x1011vp) gene transfer (GT). Corresponding GTs were also done in healthy non-ischaemic rabbits (n = 10). Muscle energy metabolism and skeletal muscle perfusion were studied non-invasively before GT and at 6 and 28 days using 31P-magnetic resonance spectroscopy and contrast pulse sequence ultrasound, respectively. Oedema was quantified using modified Miles assay at sacrifice. AdPlGF increased perfusion 7.8-fold and improved aerobic capacity of ischaemic limbs 45% compared with AdLacZ controls (P < 0.05) at 6 days. In non-ischaemic limbs, strong angiogenic response to GT, including capillary arterialization and acute oedema, did not impair muscle energy metabolism.

Conclusion: This study shows that proangiogenic gene therapy can significantly improve performance of ischaemic limbs and supports the concept of therapeutic angiogenesis for the treatment of patients with ischaemia.

KEYWORDS Gene therapy; Energy metabolism; Magnetic resonance spectroscopy; Vascular endothelial growth factors; Angiogenesis

Time for primary review: 52 days

{dagger} First two Authors contributed equally to this work


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