title: Adrenomedullin enhances angiogenic potency of bone marrow transplantation in a rat model of hindlimb ischemia.
abstract: BACKGROUND
  Previous studies have shown that adrenomedullin (AM) inhibits vascular endothelial cell apoptosis and induces angiogenesis. We investigated whether AM enhances bone marrow cell-induced angiogenesis.
  
  
  RESULTS
  Immediately after hindlimb ischemia was created, rats were randomized to receive AM infusion plus bone marrow-derived mononuclear cell (MNC) transplantation (AM+MNC group), AM infusion alone (AM group), MNC transplantation alone (MNC group), or vehicle infusion (control group). The laser Doppler perfusion index was significantly higher in the AM and MNC groups than in the control group (0.74+/-0.11 and 0.69+/-0.07 versus 0.59+/-0.07, respectively, P<0.01), which suggests the angiogenic potency of AM and MNC. Importantly, improvement in blood perfusion was marked in the AM+MNC group (0.84+/-0.08). Capillary density was highest in the AM+MNC group, followed by the AM and MNC groups. In vitro, AM inhibited MNC apoptosis, promoted MNC adhesiveness to a human umbilical vein endothelial cell monolayer, and increased the number of MNC-derived endothelial progenitor cells. In vivo, AM administration not only enhanced the differentiation of MNC into endothelial cells but also produced mature vessels that included smooth muscle cells.
  
  
  CONCLUSIONS
  A combination of AM infusion and MNC transplantation caused significantly greater improvement in hindlimb ischemia than MNC transplantation alone. This effect may be mediated in part by the angiogenic potency of AM itself and the beneficial effects of AM on the survival, adhesion, and differentiation of transplanted MNCs.
authors.affiliation: Department of Regenerative Medicine and Tissue Engineering, National Cardiovascular Center Research Institute, Suita, Osaka, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Iwase
authors.forename: Noritoshi
authors.initials: N
authors.lastname: Nagaya
authors.forename: Takafumi
authors.initials: T
authors.lastname: Fujii
authors.forename: Takefumi
authors.initials: T
authors.lastname: Itoh
authors.forename: Hatsue
authors.initials: H
authors.lastname: Ishibashi-Ueda
authors.forename: Masakazu
authors.initials: M
authors.lastname: Yamagishi
authors.forename: Kunio
authors.initials: K
authors.lastname: Miyatake
authors.forename: Toshio
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Soichiro
authors.initials: S
authors.lastname: Kitamura
authors.forename: Kenji
authors.initials: K
authors.lastname: Kangawa
mesh_terms: D053607:Adrenomedullin; D043925:Angiogenesis Inducing Agents / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016026:Bone Marrow Transplantation; D002448:Cell Adhesion; D002454:Cell Differentiation; D002465:Cell Movement; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D042783:Endothelial Cells / Q000473:pathology / Q000502:physiology; D006614:Hindlimb / Q000098:blood supply*; D006801:Humans; D007511:Ischemia / Q000628:therapy*; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010455:Peptides / Q000627:therapeutic use*; D016491:Peripheral Vascular Diseases / Q000628:therapy*; D011897:Random Allocation; D051381:Rats; D011917:Rats, Inbred Lew; D013234:Stem Cells / Q000473:pathology / Q000502:physiology; D014471:Umbilical Veins / Q000166:cytology; D014665:Vasodilator Agents / Q000627:therapeutic use*
chemical_list: D043925:Angiogenesis Inducing Agents; D010455:Peptides; D014665:Vasodilator Agents; D053607:Adrenomedullin