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(Circulation. 2004;109:526-531.)
© 2004 American Heart Association, Inc.

Basic Science Reports

Adrenomedullin Gene Transfer Induces Therapeutic Angiogenesis in a Rabbit Model of Chronic Hind Limb Ischemia

Benefits of a Novel Nonviral Vector, Gelatin

Noriyuki Tokunaga, MD; Noritoshi Nagaya, MD; Mikiyasu Shirai, MD; Etsuro Tanaka, MD; Hatsue Ishibashi-Ueda, MD; Mariko Harada-Shiba, MD; Munetake Kanda, MD; Takefumi Ito, MD; Wataru Shimizu, MD; Yasuhiko Tabata, PhD; Masaaki Uematsu, MD; Kazuhiro Nishigami, MD; Shunji Sano, MD; Kenji Kangawa, PhD; Hidezo Mori, MD

From the Department of Cardiac Physiology, National Cardiovascular Center Research Institute, Osaka, Japan (N.T., M.S., M.K., H.M.); the Department of Cardiovascular Surgery, Okayama University Medical School, Okayama, Japan (N.T., S.S.); the Department of Regenerative Medicine and Tissue Engineering, National Cardiovascular Center Research Institute, Osaka, Japan (N.N., T.I.); the Department of Internal Medicine, National Cardiovascular Center, Osaka, Japan (N.N., W.S., K.N.); the Department of Physiology, the Research Center for Genetic Engineering and Cell Transplantation, Tokai University School of Medicine, Isehara, Japan (E.T.); the Department of Pathology, National Cardiovascular Center, Osaka, Japan (H.I.-U.); the Department of Biochemistry, National Cardiovascular Center Research Institute, Osaka, Japan (M.H.-S., K.K.); the Department of Biomaterials, Field of Tissue Engineering, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan (Y.T.); and the Cardiovascular Division, Kansai Rosai Hospital, Hyogo, Japan (M.U.).

Correspondence to Noritoshi Nagaya, MD, Department of Regenerative Medicine and Tissue Engineering or Hidezo Mori, MD, Department of Cardiac Physiology, National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan. E-mail nagayann{at}hsp.ncvc.go.jp or hidemori@ri.ncvc.go.jp

Received May 20, 2003; revision received September 25, 2003; accepted September 26, 2003.

Background— Earlier studies have shown that adrenomedullin (AM), a potent vasodilator peptide, has a variety of cardiovascular effects. However, whether AM has angiogenic potential remains unknown. This study investigated whether AM gene transfer induces therapeutic angiogenesis in chronic hind limb ischemia.

Methods and Results— Ischemia was induced in the hind limb of 21 Japanese White rabbits. Positively charged biodegradable gelatin was used to produce ionically linked DNA-gelatin complexes that could delay DNA degradation. Human AM DNA (naked AM group), AM DNA-gelatin complex (AM-gelatin group), or gelatin alone (control group) was injected into the ischemic thigh muscles. Four weeks after gene transfer, significant improvements in collateral formation and hind limb perfusion were observed in the naked AM group and AM-gelatin group compared with the control group (calf blood pressure ratio: 0.60±0.02, 0.72±0.03, 0.42±0.06, respectively). Interestingly, hind limb perfusion and capillary density of ischemic muscles were highest in the AM-gelatin group, which revealed the highest content of AM in the muscles among the three groups. As a result, necrosis of lower hind limb and thigh muscles was minimal in the AM-gelatin group.

Conclusions— AM gene transfer induced therapeutic angiogenesis in a rabbit model of chronic hind limb ischemia. Furthermore, the use of biodegradable gelatin as a nonviral vector augmented AM expression and thereby enhanced the therapeutic effects of AM gene transfer. Thus, gelatin-mediated AM gene transfer may be a new therapeutic strategy for the treatment of peripheral vascular diseases.

Key Words: peripheral vascular disease • angiogenesis • gene therapy • ischemia

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