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(Circulation Research. 2008;103:1092.)
© 2008 American Heart Association, Inc.

Integrative Physiology

Vascular Endothelial Growth Factor-A and Platelet-Derived Growth Factor-B Combination Gene Therapy Prolongs Angiogenic Effects via Recruitment of Interstitial Mononuclear Cells and Paracrine Effects Rather Than Improved Pericyte Coverage of Angiogenic Vessels

Petra Korpisalo, Henna Karvinen, Tuomas T. Rissanen, Johanna Kilpijoki, Varpu Marjomäki, Peter Baluk, Donald M. McDonald, Yihai Cao, Ulf Eriksson, Kari Alitalo, Seppo Ylä-Herttuala

From the Department of Molecular Medicine (P.K., H.K., T.T.R., J.K., S.Y.-H.), A.I. Virtanen Institute, University of Kuopio, Finland; Department of Biological and Environmental Science (V.M.), Nanoscience Center, University of Jyväskylä, Finland; Cardiovascular Research Institute, Comprehensive Cancer Center, and Department of Anatomy (P.B., D.M.M.), University of California, San Francisco; Microbiology and Tumor Biology Center Karolinska Institute (Y.C.), Stockholm, Sweden; Ludwig Institute for Cancer Research (U.E.), Stockholm, Sweden; Biomedicum (K.A.), University of Helsinki, Finland; Department of Medicine (S.Y.-H.), University of Kuopio, Finland; and Gene Therapy Unit (S.Y.-H.), Kuopio University, Finland.

Correspondence to Seppo Ylä-Herttuala, MD, PhD, FESC, Department of Molecular Medicine, A.I. Virtanen Institute, University of Kuopio, PO Box 1627, FIN-70211 Kuopio, Finland. E-mail Seppo.Ylaherttuala{at}uku.fi

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 -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.

Key Words: angiogenesis • vascular endothelial growth factor • platelet derived growth factor • gene therapy

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