title: Zoledronate inhibits ischemia-induced neovascularization by impairing the mobilization and function of endothelial progenitor cells.
abstract: BACKGROUND
  Bisphosphonates are a class of pharmacologic compounds that are commonly used to treat postmenopausal osteoporosis and malignant osteolytic processes. Studies have shown that bone marrow-derived endothelial progenitor cells (EPCs) play a significant role in postnatal neovascularization. Whether the nitrogen-containing bisphosphonate zoledronate inhibits ischemia-induced neovascularization by modulating EPC functions remains unclear.
  
  
  RESULTS
  Unilateral hindlimb ischemia was surgically induced in wild-type mice after 2 weeks of treatment with vehicle or zoledronate (low-dose: 30 μg/kg; high-dose: 100 μg/kg). Doppler perfusion imaging demonstrated that the ischemic limb/normal side blood perfusion ratio was significantly lower in wild-type mice treated with low-dose zoledronate and in mice treated with high-dose zoledronate than in controls 4 weeks after ischemic surgery (control vs. low-dose vs. high-dose: 87±7% vs. *61±18% vs. **49±17%, *p<0.01, **p<0.005 compared to control). Capillary densities were also significantly lower in mice treated with low-dose zoledronate and in mice treated with high-dose zoledronate than in control mice. Flow cytometry analysis showed impaired mobilization of EPC-like cells (Sca-1(+)/Flk-1(+)) after surgical induction of ischemia in mice treated with zoledronate but normal levels of mobilization in mice treated with vehicle. In addition, ischemic tissue from mice that received zoledronate treatment exhibited significantly lower levels of the active form of MMP-9, lower levels of VEGF, and lower levels of phosphorylated eNOS and phosphorylated Akt than ischemic tissue from mice that received vehicle. Results of the in vitro studies showed that incubation with zoledronate inhibited the viability, migration, and tube-forming capacities of EPC.
  
  
  CONCLUSIONS
  Zoledronate inhibited ischemia-induced neovascularization by impairing EPC mobilization and angiogenic functions. These findings suggest that administration of zoledronate should be withheld in patients with ischemic events such as acute limb ischemia.
authors: Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors: Shih-Hung
authors: SH
authors: Tsai
authors: Po-Hsun
authors: PH
authors: Huang
authors: Wei-Chou
authors: WC
authors: Chang
authors: Hsiao-Ya
authors: HY
authors: Tsai
authors: Chih-Pei
authors: CP
authors: Lin
authors: Hsin-Bang
authors: HB
authors: Leu
authors: Tao-Cheng
authors: TC
authors: Wu
authors: Jaw-Wen
authors: JW
authors: Chen
authors: Shing-Jong
authors: SJ
authors: Lin
mesh_terms: D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D004164:Diphosphonates / Q000494:pharmacology*; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006614:Hindlimb / Q000098:blood supply / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007093:Imidazoles / Q000494:pharmacology*; D007511:Ischemia / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse