Published Online
on January 19, 2004

A more recent version of this article appeared on February 3, 2004

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Submitted on May 20, 2003
Revised on September 25, 2003
Accepted on September 26, 2003

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, and 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.).

^* To whom correspondence should be addressed. E-mail: nagayann{at}hsp.ncvc.go.jp.

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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