Journal
CIRCULATION RESEARCH
Volume 103, Issue 10, Pages 1092-U71Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.108.182287
Keywords
angiogenesis; vascular endothelial growth factor; platelet derived growth factor; gene therapy
Funding
- Finnish Academy
- European Union [LSHG-CT-2004-503573]
- Sigrid Juselius Foundation
- Finnish Cultural Foundation
- Aarne and Aili Turunen Foundation
- Paavo Nurmi Foundation
- Emil Aaltonen Foundation
- NIH [HL24136, HL59157]
- National Heart, Lung, and Blood Institute
- National Cancer Institute [CA82923]
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Vessel stabilization and the inhibition of side effects such as tissue edema are essential in angiogenic gene therapy. Thus, combination gene transfers stimulating both endothelial cell and pericyte proliferation have become of interest. However, there is currently little data to support combination gene transfer in large animal models. In this study, we evaluated the potential advantages of such a strategy by combining the transfer of adenoviral (Ad) vascular endothelial growth factor (VEGF)-A and platelet-derived growth factor (PDGF)-B into rabbit hindlimb skeletal muscle. AdLacZ alone or in combination with AdVEGF-A were used as controls. Contrast-enhanced ultrasound, modified Miles assay, and immunohistology were used to quantify perfusion, vascular permeability, and capillary size, respectively. Confocal microscopy was used in the assessment of pericyte-coverage. The transfer of AdPDGF-B alone and in combination with AdVEGF-A induced prominent proliferation of alpha-smooth muscle actin-, CD31-, RAM11-, HAM56-, and VEGF- positive cells. Although, pericyte recruitment to angiogenic vessels was not improved, combination gene transfer induced a longer-lasting increase in perfusion in both intact and ischemic muscles than AdVEGF-A gene transfer alone. In conclusion, intramuscular delivery of AdVEGF-A and AdPDGF-B, combined, resulted in a prolonged angiogenic response. However, the effects were most likely mediated via paracrine mechanisms rather than an increase in vascular pericyte coverage. (Circ Res. 2008; 103: 1092-1099.)
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