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Cardiovascular Research Advance Access [Accepted Manuscript] published online on July 22, 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 Ischemic Rabbit Hindlimbs

Petra Korpisalo, MD*,1, Tuomas T. Rissanen, MD, PhD*,1, Timo Bengtsson, MD1, Timo Liimatainen, PhD1, Svetlana Laidinen, MSc1, Henna Karvinen, MSc1, Johanna E. Markkanen, MD1, Olli H. Gröhn, PhD2 and Seppo Ylä-Herttuala, MD, PhD, FESC1,3,4

1 Department of Molecular Medicine, A.I. Virtanen Institute, University of Kuopio, Finland
2 Department of Neurobiology, A.I. Virtanen Institute, University of Kuopio, Finland
3 Department of Medicine, University of Kuopio, Finland
4 Gene Therapy Unit, Kuopio University, Kuopio, Finland

Address for correspondence and reprint requests: Seppo Ylä-Herttuala MD, PhD, FESC Department of Molecular Medicine, A.I. Virtanen Institute, University of Kuopio P.O. Box 1627, FIN-70211 Kuopio, Finland Phone: +358-17-162075, Fax: +358-17-163751, E-mail: Seppo.Ylaherttuala{at}uku.fi

Aims: We investigated effects of angiogenic gene therapy with adenoviral placental growth factor131 (AdPlGF) on aerobic capacity and exercise tolerance in a rabbit hindlimb ischemia 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: Hindlimb ischemia was surgically induced in New Zealand White rabbits (n=20) that a day later received i.m. AdPlGF or AdLacZ (3x1011vp) gene transfer (GT). Corresponding GTs were done in healthy non-ischemic 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. Edema was quantified using modified Miles assay at sacrifice.

Results: AdPlGF increased perfusion 7.8-fold and improved aerobic capacity of ischemic limbs 45% compared to AdLacZ controls (P<0.05) at six days. In non-ischemic limbs, strong angiogenic response to GT, including capillary arterialisation and acute edema, did not impair muscle energy metabolism.

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

Time for primary review: 52 days

* Authors with equal contribution


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