Capillary enlargement, not sprouting angiogenesis, determines beneficial therapeutic effects and side effects of angiogenic gene therapy

Aims Currently, it is still unclear which mechanisms drive metabolic benefits after angiogenic gene therapy. The side-effect profile of efficient angiogenic gene therapy is also currently incompletely understood. In this study, the effects of increasing doses of adenoviral (Ad) vascular endothelial...

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Published in:European heart journal 2011-07, Vol.32 (13), p.1664-1672
Main Authors: Korpisalo, Petra, Hytönen, Jarkko P., Laitinen, Johannes T.T., Laidinen, Svetlana, Parviainen, Henna, Karvinen, Henna, Siponen, Jaana, Marjomäki, Varpu, Vajanto, Ismo, Rissanen, Tuomas T., Ylä-Herttuala, Seppo
Format: Article
Language:English
Subjects:
Adenoviridae
Animals
Biological and medical sciences
Capillaries - anatomy & histology
Cardiology. Vascular system
Dose-Response Relationship, Drug
Enzyme-Linked Immunosorbent Assay
Gene Transfer Techniques
Genetic Therapy - adverse effects
Genetic Therapy - methods
Genetic Vectors
Hindlimb
Injections, Intramuscular
Lac Operon - genetics
Medical sciences
Muscle, Skeletal - blood supply
Neovascularization, Physiologic
Rabbits
Ultrasonography, Interventional
Vascular Endothelial Growth Factor A - administration & dosage
Vascular Endothelial Growth Factor A - adverse effects
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Summary:Aims Currently, it is still unclear which mechanisms drive metabolic benefits after angiogenic gene therapy. The side-effect profile of efficient angiogenic gene therapy is also currently incompletely understood. In this study, the effects of increasing doses of adenoviral (Ad) vascular endothelial growth factor-A (VEGF-A) were evaluated on vascular growth, metabolic benefits, and systemic side effects. Methods and results Adenoviral vascular endothelial growth factor-A or AdLacZ control was injected intramuscularly (109-1011 vp/mL) or intra-arterially (5 × 1011 vp/mL) into rabbit (n = 102) hindlimb muscles and examined 6 or 14 days later. Blood flow, tissue oedema, metabolic benefits, and the structure of angiogenic vessels were assessed using ultrasound imaging, modified Miles assay, arterial blood gas and metabolite analyses, and light and confocal microscopy, respectively. Safety analyses included cardiac ultrasound, electrocardiograms, and blood and tissue samples. Sprouting angiogenesis was already induced with low AdVEGF-A concentrations, whereas higher concentrations were needed to reach efficient capillary enlargement and increases in target muscle perfusion. Interestingly, metabolic benefits, such as improved aerobic energy metabolism and decreased metabolic acidosis during exercise, after AdVEGF-A administration were highly correlated to the level of capillary enlargement but not to sprouting angiogenesis. Several systemic dose-dependent side effects, including transient increases in liver, kidney, and pancreatic enzymes, and signs of cardiac effects were observed. Conclusion Efficient capillary enlargement leading to significant increases in tissue perfusion is needed to gain metabolic benefits after angiogenic gene therapy. However, the risk of systemic side effects can increase as the efficiency of angiogenic gene therapy is improved. Importantly, the unstable wall structure of the newly formed vessels seems not to compromise the metabolic benefits.
ISSN:0195-668X
1522-9645
DOI:10.1093/eurheartj/ehq433