Cargando…

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

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....

Descripción completa

Detalles Bibliográficos
Autores principales: Tsai, Shih-Hung, Huang, Po-Hsun, Chang, Wei-Chou, Tsai, Hsiao-Ya, Lin, Chih-Pei, Leu, Hsin-Bang, Wu, Tao-Cheng, Chen, Jaw-Wen, Lin, Shing-Jong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3405104/
https://www.ncbi.nlm.nih.gov/pubmed/22848429
http://dx.doi.org/10.1371/journal.pone.0041065
_version_ 1782239084809289728
author Tsai, Shih-Hung
Huang, Po-Hsun
Chang, Wei-Chou
Tsai, Hsiao-Ya
Lin, Chih-Pei
Leu, Hsin-Bang
Wu, Tao-Cheng
Chen, Jaw-Wen
Lin, Shing-Jong
author_facet Tsai, Shih-Hung
Huang, Po-Hsun
Chang, Wei-Chou
Tsai, Hsiao-Ya
Lin, Chih-Pei
Leu, Hsin-Bang
Wu, Tao-Cheng
Chen, Jaw-Wen
Lin, Shing-Jong
author_sort Tsai, Shih-Hung
collection PubMed
description 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.
format Online
Article
Text
id pubmed-3405104
institution National Center for Biotechnology Information
language English
publishDate 2012
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-34051042012-07-30 Zoledronate Inhibits Ischemia-Induced Neovascularization by Impairing the Mobilization and Function of Endothelial Progenitor Cells Tsai, Shih-Hung Huang, Po-Hsun Chang, Wei-Chou Tsai, Hsiao-Ya Lin, Chih-Pei Leu, Hsin-Bang Wu, Tao-Cheng Chen, Jaw-Wen Lin, Shing-Jong PLoS One Research Article 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. Public Library of Science 2012-07-25 /pmc/articles/PMC3405104/ /pubmed/22848429 http://dx.doi.org/10.1371/journal.pone.0041065 Text en Tsai et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Tsai, Shih-Hung
Huang, Po-Hsun
Chang, Wei-Chou
Tsai, Hsiao-Ya
Lin, Chih-Pei
Leu, Hsin-Bang
Wu, Tao-Cheng
Chen, Jaw-Wen
Lin, Shing-Jong
Zoledronate Inhibits Ischemia-Induced Neovascularization by Impairing the Mobilization and Function of Endothelial Progenitor Cells
title Zoledronate Inhibits Ischemia-Induced Neovascularization by Impairing the Mobilization and Function of Endothelial Progenitor Cells
title_full Zoledronate Inhibits Ischemia-Induced Neovascularization by Impairing the Mobilization and Function of Endothelial Progenitor Cells
title_fullStr Zoledronate Inhibits Ischemia-Induced Neovascularization by Impairing the Mobilization and Function of Endothelial Progenitor Cells
title_full_unstemmed Zoledronate Inhibits Ischemia-Induced Neovascularization by Impairing the Mobilization and Function of Endothelial Progenitor Cells
title_short Zoledronate Inhibits Ischemia-Induced Neovascularization by Impairing the Mobilization and Function of Endothelial Progenitor Cells
title_sort zoledronate inhibits ischemia-induced neovascularization by impairing the mobilization and function of endothelial progenitor cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3405104/
https://www.ncbi.nlm.nih.gov/pubmed/22848429
http://dx.doi.org/10.1371/journal.pone.0041065
work_keys_str_mv AT tsaishihhung zoledronateinhibitsischemiainducedneovascularizationbyimpairingthemobilizationandfunctionofendothelialprogenitorcells
AT huangpohsun zoledronateinhibitsischemiainducedneovascularizationbyimpairingthemobilizationandfunctionofendothelialprogenitorcells
AT changweichou zoledronateinhibitsischemiainducedneovascularizationbyimpairingthemobilizationandfunctionofendothelialprogenitorcells
AT tsaihsiaoya zoledronateinhibitsischemiainducedneovascularizationbyimpairingthemobilizationandfunctionofendothelialprogenitorcells
AT linchihpei zoledronateinhibitsischemiainducedneovascularizationbyimpairingthemobilizationandfunctionofendothelialprogenitorcells
AT leuhsinbang zoledronateinhibitsischemiainducedneovascularizationbyimpairingthemobilizationandfunctionofendothelialprogenitorcells
AT wutaocheng zoledronateinhibitsischemiainducedneovascularizationbyimpairingthemobilizationandfunctionofendothelialprogenitorcells
AT chenjawwen zoledronateinhibitsischemiainducedneovascularizationbyimpairingthemobilizationandfunctionofendothelialprogenitorcells
AT linshingjong zoledronateinhibitsischemiainducedneovascularizationbyimpairingthemobilizationandfunctionofendothelialprogenitorcells