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Lack of thrombospondin-1 increases angiogenesis in a model of chronic inflammatory bowel disease

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International Journal of Colorectal Disease Aims and scope Submit manuscript

Abstract

Background and aims

Vascular abnormalities and expression of pro-angiogenic factors are observed in inflammatory bowel diseases (IBD). In this study, the role of thrombospondin-1 (TSP-1), an antiangiogenic protein, was analyzed using the dextran sulfate sodium (DSS) model for IBD.

Materials and methods

Wild-type (WT) and thrombospondin-1-deficient (TSP-1-/-) mice were subjected to four cycles (7 days) of DSS. Basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), transforming growth factor beta 1 (TGFß-1), and pro-apoptotic proteins such as Fas and its ligand (FasL) were determined by enzyme-linked immunosorbent assay. Double immunohistochemistry for cluster of differential 31 (CD31) and panendothelial cell antigen-32 antibodies was performed for detecting blood vessels. The terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay was also performed for identifying apoptotic cells. Inflammation, dysplasia, microvascular density (MVD), apoptotic indices (AI), protein 53 (p53), and ß-catenin expression were determined.

Results

VEGF and bFGF protein levels and MVD were higher in the TSP-1-/- mice (p = 0.0312, p = 0.0246, and p = 0.0085, respectively). AI in the endothelial cells (EC) and FasL levels were significantly lower in TSP-1-/- compared to WT mice (p = 0.0042 and p = 0.0362, respectively). Dysplasia was detected in 66% of TSP-1-/- mice compared to 14% in WT mice. Hscores of ß-catenin and areas overexpressing p53 were higher in TSP-1-/- mice (p = 0.0002 and p = 0.0339, respectively).

Conclusion

TSP-1 may decrease angiogenesis by reducing the levels of pro-angiogenic factors and inducing apoptosis in EC through the Fas or FasL pathway. These findings, along with the increased overexpression of p53 and ß-catenin in TSP-1-/- mice, underline its role in carcinogenesis.

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Acknowledgements

This work has been supported by a National Institutes of Health grant DK067901, a Wilkes University Mentoring grant, and institutional funding from the departments of Biology and Pharmaceutical Sciences at Wilkes University.

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Authors and Affiliations

  1. Department of Biology, Wilkes University, 84 W. South St., Wilkes-Barre, PA, USA

    Samantha Zak, John Treven, Nolly Nash & Linda S. Gutierrez

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  1. Samantha Zak
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  2. John Treven
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  3. Nolly Nash
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  4. Linda S. Gutierrez
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Correspondence to Linda S. Gutierrez.

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Zak, S., Treven, J., Nash, N. et al. Lack of thrombospondin-1 increases angiogenesis in a model of chronic inflammatory bowel disease. Int J Colorectal Dis 23, 297–304 (2008). https://doi.org/10.1007/s00384-007-0397-5

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