Adrenomedullin gene transfer induces therapeutic angiogenesis in a rabbit model of chronic hind limb ischemia: benefits of a novel nonviral vector, gelatin.
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.


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.
Tokunaga
Noriyuki
N
Department of Cardiac Physiology, National Cardiovascular Center Research Institute, Osaka, Japan.
Nagaya
Noritoshi
N
Shirai
Mikiyasu
M
Tanaka
Etsuro
E
Ishibashi-Ueda
Hatsue
H
Harada-Shiba
Mariko
M
Kanda
Munetake
M
Ito
Takefumi
T
Shimizu
Wataru
W
Tabata
Yasuhiko
Y
Uematsu
Masaaki
M
Nishigami
Kazuhiro
K
Sano
Shunji
S
Kangawa
Kenji
K
Mori
Hidezo
H
D053607:Adrenomedullin; D000818:Animals; D002908:Chronic Disease; D005780:Gelatin; D015870:Gene Expression; D005822:Genetic Vectors; D007511:Ischemia / Q000000981:diagnostic imaging / Q000473:pathology / Q000628:therapy*; D035002:Lower Extremity / Q000098:blood supply*; D008297:Male; D018919:Neovascularization, Physiologic; D010455:Peptides / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011817:Rabbits; D011859:Radiography
D010455:Peptides; D011518:Proto-Oncogene Proteins; D053607:Adrenomedullin; D005780:Gelatin; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt