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* Baxter Laboratory in Genetic Pharmacology, Departments of Molecular Pharmacology and of Microbiology and Immunology;
Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA;
Cardiovascular Research, Bayer Healthcare, Wuppertal, Germany;
Institute for Surgical Research and Hospital Management, Department of Research and Department of Surgery, University Hospital, Basel, Switzerland; and
|| Division of Cardiology, University of California, San Francisco, California, USA
1Correspondence: Baxter Laboratory in Genetic Pharmacology, Stanford University School of Medicine, Stanford, CA 94305-5175, USA. E-mail: hblau{at}stanford.edu
ABSTRACT
The critical role of vascular endothelial growth factor (VEGF) expression levels in developmental angiogenesis is well established. Nonetheless, the effects of different local (microenvironmental) VEGF concentrations in ischemia have not been studied in the adult organism, and VEGF delivery to patients has been disappointing. Here, we demonstrate the existence of both lower and upper threshold levels of microenvironmental VEGF concentrations for the induction of therapeutic vessel growth in ischemia. In the ischemic hind limb, implantation of myoblasts transduced to express VEGF164 at different levels per cell increased blood flow only moderately, and vascular leakage and aberrant preangiomatous vessels were always induced. When the same total dose was uniformly distributed by implanting a monoclonal population derived from a single VEGF-expressing myoblast, blood flow was fully restored to nonischemic levels, collateral growth was induced, and ischemic damage was prevented. Hemangiomas were avoided and only normal, pericyte-covered vessels were induced persisting over 15 mo. Surprisingly, clones uniformly expressing either lower or higher VEGF levels failed to provide any functional benefit. A biphasic effect of VEGF dose on vessel number and diameter was found. Blood flow was only improved if vessels were increased both in size and in number. Microenvironmental VEGF concentrations determine efficacy and safety in a therapeutic setting.—von Degenfeld, G., Banfi, A., Springer, M. L., Wagner, R. A., Jacobi, J., Ozawa, C. R., Merchant, M. J., Cooke, J. P., Blau, H. M. Microenvironmental VEGF distribution is critical for stable and functional vessel growth in ischemia.
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