Therapeutic angiogenesis with placental growth factor improves exercise tolerance of ischaemic rabbit hindlimbs.
OBJECTIVE
We investigated the effects of angiogenic gene therapy with adenoviral placental growth factor(131) (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.


RESULTS
Hindlimb ischaemia was surgically induced in New Zealand White rabbits (n = 20) that a day later received intramuscular (i.m.) AdPlGF or AdLacZ (3 x 10(11)vp) 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 (31)P-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.


CONCLUSIONS
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.
Korpisalo
Petra
P
Department of Molecular Medicine, A.I. Virtanen Institute, University of Kuopio, PO Box 1627, FIN-70211 Kuopio, Finland.
Rissanen
Tuomas T
TT
Bengtsson
Timo
T
Liimatainen
Timo
T
Laidinen
Svetlana
S
Karvinen
Henna
H
Markkanen
Johanna E
JE
Gröhn
Olli H
OH
Ylä-Herttuala
Seppo
S
D000138:Acidosis / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D004487:Edema / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D004734:Energy Metabolism; D017079:Exercise Tolerance; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D005822:Genetic Vectors; D006614:Hindlimb; D007511:Ischemia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D018482:Muscle, Skeletal / Q000098:blood supply*; D018919:Neovascularization, Physiologic; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000096:biosynthesis* / Q000235:genetics; D011817:Rabbits; D012039:Regional Blood Flow; D013997:Time Factors
C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D000072483:Placenta Growth Factor