Zoledronate Inhibits Ischemia-Induced Neovascularization by Impairing the Mobilization and Function of Endothelial Progenitor Cells

被引：19

作者：

Tsai, Shih-Hung ^{[1
,2
]}

Huang, Po-Hsun ^{[2
,3
,4
]}

Chang, Wei-Chou ^{[5
]}

Tsai, Hsiao-Ya ^{[2
,4
]}

Lin, Chih-Pei ^{[6
,7
,8
]}

Leu, Hsin-Bang ^{[2
,3
,4
,9
]}

Wu, Tao-Cheng ^{[3
,4
]}

Chen, Jaw-Wen ^{[3
,4
,7
,8
,10
]}

Lin, Shing-Jong ^{[2
,3
,4
,10
]}

机构：

[1] Tri Serv Gen Hosp, Natl Def Med Ctr, Dept Emergency Med, Taipei, Taiwan

[2] Natl Yang Ming Univ, Inst Clin Med, Taipei 112, Taiwan

[3] Taipei Vet Gen Hosp, Div Cardiol, Dept Internal Med, Taipei, Taiwan

[4] Natl Yang Ming Univ, Cardiovasc Res Ctr, Taipei 112, Taiwan

[5] Tri Serv Gen Hosp, Natl Def Med Ctr, Dept Radiol, Taipei, Taiwan

[6] Taipei Vet Gen Hosp, Div Gen Lab, Dept Pathol & Lab Med, Taipei, Taiwan

[7] Natl Yang Ming Univ, Inst Pharmacol, Taipei 112, Taiwan

[8] Natl Yang Ming Univ, Dept Pharmacol, Taipei 112, Taiwan

[9] Taipei Vet Gen Hosp, Healthcare & Management Ctr, Taipei, Taiwan

[10] Taipei Vet Gen Hosp, Dept Med Res & Educ, Taipei, Taiwan

来源：

PLOS ONE | 2012年 / 7卷 / 07期

关键词：

GROWTH-FACTOR; PAGETS-DISEASE; BONE; ACID; MATRIX-METALLOPROTEINASE-9; BISPHOSPHONATES; ANGIOGENESIS; OSTEOCLASTS; MICE; PAMIDRONATE;

D O I：

10.1371/journal.pone.0041065

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 mu g/kg; high-dose: 100 mu g/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.

引用

页数：11