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.
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 bisphosphonatezoledronate 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.
Authors: T Asahara; H Masuda; T Takahashi; C Kalka; C Pastore; M Silver; M Kearne; M Magner; J M Isner Journal: Circ Res Date: 1999-08-06 Impact factor: 17.367
Authors: Martha Q Lacy; Angela Dispenzieri; Morie A Gertz; Philip R Greipp; Kimberly L Gollbach; Suzanne R Hayman; Shaji Kumar; John A Lust; S Vincent Rajkumar; Stephen J Russell; Thomas E Witzig; Steven R Zeldenrust; David Dingli; P Lief Bergsagel; Rafael Fonseca; Craig B Reeder; A Keith Stewart; Vivek Roy; Robert J Dalton; Alan B Carr; Deepak Kademani; Eugene E Keller; Christopher F Viozzi; Robert A Kyle Journal: Mayo Clin Proc Date: 2006-08 Impact factor: 7.616
Authors: T Asahara; T Murohara; A Sullivan; M Silver; R van der Zee; T Li; B Witzenbichler; G Schatteman; J M Isner Journal: Science Date: 1997-02-14 Impact factor: 47.728
Authors: Beate Heissig; Koichi Hattori; Sergio Dias; Matthias Friedrich; Barbara Ferris; Neil R Hackett; Ronald G Crystal; Peter Besmer; David Lyden; Malcolm A S Moore; Zena Werb; Shahin Rafii Journal: Cell Date: 2002-05-31 Impact factor: 41.582
Authors: Viviana Ribeiro; Mónica Garcia; Raquel Oliveira; Pedro S Gomes; Bruno Colaço; Maria Helena Fernandes Journal: J Cell Mol Med Date: 2013-10-31 Impact factor: 5.310