%0 Journal Article %1 10.1371/journal.pone.0041065 %A Tsai, Shih-Hung %A Huang, Po-Hsun %A Chang, Wei-Chou %A Tsai, Hsiao-Ya %A Lin, Chih-Pei %A Leu, Hsin-Bang %A Wu, Tao-Cheng %A Chen, Jaw-Wen %A Lin, Shing-Jong %D 2012 %I Public Library of Science %J PLOS ONE %K epcs %N 7 %P 1-11 %R 10.1371/journal.pone.0041065 %T Zoledronate Inhibits Ischemia-Induced Neovascularization by Impairing the Mobilization and Function of Endothelial Progenitor Cells %U https://doi.org/10.1371/journal.pone.0041065 %V 7 %X 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. Methodology/Principal Findings 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/Significance 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.

@article{10.1371/journal.pone.0041065, 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. Methodology/Principal Findings 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/Significance 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.}, added-at = {2017-09-21T09:04:20.000+0200}, author = {Tsai, Shih-Hung and Huang, Po-Hsun and Chang, Wei-Chou and Tsai, Hsiao-Ya and Lin, Chih-Pei and Leu, Hsin-Bang and Wu, Tao-Cheng and Chen, Jaw-Wen and Lin, Shing-Jong}, biburl = {https://www.bibsonomy.org/bibtex/2879b4f88864927dd97c72c3cbee2285e/fengningren-001}, description = {Zoledronate Inhibits Ischemia-Induced Neovascularization by Impairing the Mobilization and Function of Endothelial Progenitor Cells}, doi = {10.1371/journal.pone.0041065}, interhash = {5a0adc61558e4246c938f16947bac620}, intrahash = {879b4f88864927dd97c72c3cbee2285e}, journal = {PLOS ONE}, keywords = {epcs}, month = {07}, number = 7, pages = {1-11}, publisher = {Public Library of Science}, timestamp = {2017-09-21T09:04:20.000+0200}, title = {Zoledronate Inhibits Ischemia-Induced Neovascularization by Impairing the Mobilization and Function of Endothelial Progenitor Cells}, url = {https://doi.org/10.1371/journal.pone.0041065}, volume = 7, year = 2012 }