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Angiostatin inhibits experimental liver fibrosis in mice

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International Journal of Colorectal Disease Aims and scope Submit manuscript

Abstract

Background and aims

Liver fibrosis is a response to chronic hepatic damage, which ultimately leads to liver failure and necessitates liver transplantation. A characteristic of fibrosis is pathological vessel growth. This type of angiogenesis may contribute to the disturbance of hepatocyte perfusion dynamics and lead to aggravation of disease. We hypothesized that angiostatin can inhibit pathological vessel growth and, consequently, the development of hepatic fibrosis.

Methods

Hepatic fibrosis was induced by injection of carbon tetrachloride for 5 weeks. Angiostatin mice received carbon tetrachloride for 5 weeks and angiostatin during weeks 4 and 5. After 5 weeks, immunohistochemistry for endothelial cell marker von Willebrand factor and for cell proliferation was performed. Angiogenesis was quantified by counting the number of immunopositive microvessels. Also, the relative fibrotic surface was determined using Sirius Red histostaining and computer image analysis.

Results

Immunohistochemistry revealed increased expression for von Willebrand factor in fibrotic livers. Immunopositive microvessels were localized in fibrotic areas surrounding larger vessels and in emerging fibrotic septa. Angiostatin reduced the number of immunopositive microvessels by 69% (p<0.001). In addition, angiostatin reduced the relative fibrotic area in the liver by 63±0.1% (p<0.001). Finally, angiostatin treatment was not associated with differences in cell proliferation.

Conclusions

Angiostatin inhibits the development of pathological angiogenesis and liver fibrosis in mice. These results warrant further evaluation of angiostatin as an antifibrotic agent, potentially contributing to the deferment of liver transplantation and reduced recurrence of fibrotic disease in the transplanted liver.

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Acknowledgements

We thank S. Smulders for technical assistance with histological procedures.

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Authors and Affiliations

  1. Department of Surgery, University Medical Center Utrecht, PO Box 85500, 3508 GA, Utrecht, The Netherlands

    J. Mathys Vogten, Tamas A. Drixler, Elisabeth A. te Velde, Theo J. M. V. van Vroonhoven & Inne H. M. Borel Rinkes

  2. Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands

    Marguerite E. Schipper

  3. Laboratory of Oncology, University Medical Center Utrecht, Utrecht, The Netherlands

    Emile E. Voest

Authors
  1. J. Mathys Vogten
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  2. Tamas A. Drixler
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  3. Elisabeth A. te Velde
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  4. Marguerite E. Schipper
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  5. Theo J. M. V. van Vroonhoven
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  6. Emile E. Voest
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  7. Inne H. M. Borel Rinkes
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Correspondence to Inne H. M. Borel Rinkes.

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Vogten, J.M., Drixler, T.A., te Velde, E.A. et al. Angiostatin inhibits experimental liver fibrosis in mice. Int J Colorectal Dis 19, 387–394 (2004). https://doi.org/10.1007/s00384-003-0562-4

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  • DOI: https://doi.org/10.1007/s00384-003-0562-4

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