Published online before print April 25, 2002, doi: 10.1161/01.RES.0000019540.41697.60
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© 2002 American Heart Association, Inc.
Integrative Physiology |
Angiogenic Gene Therapy for Experimental Critical Limb Ischemia
Acceleration of Limb Loss by Overexpression of Vascular Endothelial Growth Factor 165 but not of Fibroblast Growth Factor-2
From the Department of Pathology (I.M., Y.Y., A.Y., S.S., M.T., K.N., K. Sueishi), Division of Pathophysiological and Experimental Pathology, and the Department of Surgery and Science (I.M., K.K., K. Sugimachi), Graduate School of Medical Sciences, Kyushu University, Fukuoka; DNAVEC Research Inc (X.H., M.H.), Tsukuba, Ibaraki; and the National Institute of Infectious Diseases (Y.N.), Tokyo, Japan.
Correspondence to Yoshikazu Yonemitsu, MD, PhD, Division of Pathophysiological and Experimental Pathology, Dept of Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail yonemitu{at}pathol1.med.kyushu-u.ac.jp
Recent studies suggest the possible therapeutic effect of intramuscular vascular endothelial growth factor (VEGF) gene transfer in individuals with critical limb ischemia. Little information, however, is available regarding (1) the required expression level of VEGF for therapeutic effect, (2) the related expression of endogenous angiogenic factors, including fibroblast growth factor-2 (FGF-2), and (3) the related adverse effects due to overexpression of VEGF. To address these issues, we tested effects of overexpression of VEGF165 using recombinant Sendai virus (SeV), as directly compared with FGF-2 gene transfer. Intramuscular injection of SeV strongly boosted FGF-2, resulting in significant therapeutic effects for limb salvage with increased blood perfusion associated with enhanced endogenous VEGF expression in murine models of critical limb ischemia. In contrast, VEGF165 overexpression, 5-times higher than that of baseline on day 1, also strongly evoked endogenous VEGF in muscles, resulting in an accelerated limb amputation without recovery of blood perfusion. Interestingly, viable skeletal muscles of either VEGF165- or FGF-2–treated ischemic limbs showed similar platelet-endothelial cell adhesion molecule-1–positive vessel densities. Maturation of newly formed vessels suggested by smooth muscle cell actin–positive cell lining, however, was significantly disturbed in muscles with VEGF. Further, therapeutic effects of FGF-2 were completely diminished by anti-VEGF neutralizing antibody in vivo, thus indicating that endogenous VEGF does contribute to the effect of FGF-2. These results suggest that VEGF is necessary, but should be delicately regulated to lower expression to treat ischemic limb. The therapeutic effect of FGF-2, associated with the harmonized angiogenic effects seen with endogenous VEGF, provides important insights into therapeutic angiogenesis.
Key Words: angiogenesis • vascular endothelial growth factor • fibroblast growth factor-2 • limb ischemia • limb salvage
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