title: Adrenomedullin gene transfer induces therapeutic angiogenesis in a rabbit model of chronic hind limb ischemia: benefits of a novel nonviral vector, gelatin.
abstract: 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.
authors.affiliation: Department of Cardiac Physiology, National Cardiovascular Center Research Institute, Osaka, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Tokunaga
authors.forename: Noritoshi
authors.initials: N
authors.lastname: Nagaya
authors.forename: Mikiyasu
authors.initials: M
authors.lastname: Shirai
authors.forename: Etsuro
authors.initials: E
authors.lastname: Tanaka
authors.forename: Hatsue
authors.initials: H
authors.lastname: Ishibashi-Ueda
authors.forename: Mariko
authors.initials: M
authors.lastname: Harada-Shiba
authors.forename: Munetake
authors.initials: M
authors.lastname: Kanda
authors.forename: Takefumi
authors.initials: T
authors.lastname: Ito
authors.forename: Wataru
authors.initials: W
authors.lastname: Shimizu
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Tabata
authors.forename: Masaaki
authors.initials: M
authors.lastname: Uematsu
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nishigami
authors.forename: Shunji
authors.initials: S
authors.lastname: Sano
authors.forename: Kenji
authors.initials: K
authors.lastname: Kangawa
authors.forename: Hidezo
authors.initials: H
authors.lastname: Mori
mesh_terms: 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
chemical_list: D010455:Peptides; D011518:Proto-Oncogene Proteins; D053607:Adrenomedullin; D005780:Gelatin; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt