title: Deferoxamine promotes angiogenesis via the activation of vascular endothelial cell function.
abstract: BACKGROUND
  Deferoxamine (DFO), an iron chelator for disorders of excess iron, upregulates the expression of angiogenic factors, such as vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2), indicating that it affects angiogenesis. Herein, we clarify the effect and mechanism of action of DFO on angiogenesis.
  
  
  RESULTS
  In an in vitro study, DFO increased endothelial nitric oxide synthesis (eNOS) phosphorylation in human aortic endothelial cells (HAECs), which were inhibited by the phosphatidylinositol 3-kinase inhibitor LY294002. Tube formation, cell proliferation, and cell migration in HAECs were promoted by DFO, which were significantly reduced by LY294002. In an in vivo study, DFO promoted blood flow recovery in response to the hindlimb ischemia in mice with unilateral hindlimb surgery. The density of capillaries and arterioles in ischemic muscle was higher in DFO-treated mice compared to vehicle-treated mice. Endothelial cell proliferation increased and oxidative stress and apoptosis decreased in ischemic muscles of DFO-treated mice. The phosphorylation of Akt and eNOS on the ischemic side was elevated and urinary nitric oxide/nitric dioxide (NOx) excretion was higher in DFO-treated mice compared to vehicle-treated mice. The effect of DFO on angiogenesis was abolished in eNOS-deficient mice with hindlimb ischemia.
  
  
  CONCLUSIONS
  These findings indicate that DFO promotes revascularization via the activation of vascular endothelial cell function by an Akt-eNOS-dependent mechanism.
authors.affiliation: Department of Pharmacology, University of Tokushima Graduate School of Health Biosciences, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan. yasuike@basic.med.tokushima-u.ac.jp
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Soichiro
authors.initials: S
authors.lastname: Tajima
authors.forename: Sumiko
authors.initials: S
authors.lastname: Yoshida
authors.forename: Noriko
authors.initials: N
authors.lastname: Yamano
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Kihira
authors.forename: Keisuke
authors.initials: K
authors.lastname: Ishizawa
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Aihara
authors.forename: Shuhei
authors.initials: S
authors.lastname: Tomita
authors.forename: Koichiro
authors.initials: K
authors.lastname: Tsuchiya
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Tamaki
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003676:Deferoxamine / Q000494:pharmacology*; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D007502:Iron Chelating Agents / Q000494:pharmacology*; D007511:Ischemia / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000098:blood supply; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
chemical_list: D007502:Iron Chelating Agents; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D003676:Deferoxamine