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Alterations in Heparan Sulfate in the Vessel in Response to Vascular Injury in the Mouse

Abstract

Heparan sulfate (HS) is ubiquitous throughout the human body. The backbone of HS is composed of many types of sugars. HS serves as a docking site for a vast array of protein ligands. Recent evidence suggests a unique diversity in HS structure that alters protein binding and protein function. This diversity in HS structure has been overlooked till now. The goal of this study was to determine whether femoral artery wire injury modified HS structure. Femoral artery wire injury was performed in 16-week-old male C57BL6 mice. Transcript levels of a panel of enzymes that regulate HS fine structure, including N-deacetylase-N-sulfotransferases (Ndst) 1 and 2, exostoses (Ext) 1 and 2, C5 epimerase, and 2-O and 6-O sulfotransferases, were quantified with real-time quantitative polymerase chain reaction at 7 and 14 days post injury. All enzymes showed significant alterations in messenger RNA expression in response to injury. Ndst1, the most prevalent isoform, exhibited a 20-fold increase in response to injury. Injury induced significant alterations in fine structure specially increases in N-sulfated disaccharides at 14 days post injury. Vascular injury invokes transcriptional regulation of the enzymes that regulate HS structure, as well as changes in the pattern of HS chains in the vessel wall 14 days post injury. These findings may be important as the foundation of altered growth factor and chemokine binding in the process of vascular remodeling.

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References

  1. Esko, J. D., & Selleck, S. (2002). Order out of chaos: Assembly of ligand binding sites in heparan sulfate. Annual Review of Biochemistry, 71, 435–471.

    PubMed  Article  CAS  Google Scholar 

  2. Lindahl, U., Kusche-Gullberg, M., & Kjellen, L. (1998). Regulated diversity of heparan sulfate. Journal of Biological Chemistry, 273, 24979–24982.

    PubMed  Article  CAS  Google Scholar 

  3. Selleck, S. B. (2000). Proteoglycans and pattern formation: Sugar biochemistry meets developmental genetics. Trends in Genetics, 16, 206–12.

    PubMed  Article  CAS  Google Scholar 

  4. Toyoda, H., Kinoshita-Toyoda, A., Fox, B., & Selleck, S. B. (2000). Structural analysis of glycosaminoglycans in animals bearing mutations in sugarless, sulfateless, and tout-velu. Drosophila homologues of vertebrate genes encoding glycosaminoglycan biosynthetic enzymes. Journal of Biological Chemistry, 275, 21856–21861.

    PubMed  Article  CAS  Google Scholar 

  5. Sata, M., Maejima, Y., Adachi, F., Fukino, K., Saiura, A., Sugiura, S., et al. (2000). A mouse model of vascular injury that induces rapid onset of medial cell apoptosis followed by reproducible neointimal hyperplasia. Journal of Molecular and Cellular Cardiology, 32, 2097–2104.

    PubMed  Article  CAS  Google Scholar 

  6. Lawrence, R., Lu, H., Rosenberg, R. D., Esko, J. D., & Zhang, L. (2008). Disaccharide structure code for the easy representation of constituent oligosaccharides from glycosaminoglycans. Nature Methods, 5, 291–292.

    PubMed  Article  CAS  Google Scholar 

  7. Wang, X., Adhikari, N., Li, Q., & Hall, J. L. (2004). LDL receptor-related protein LRP6 regulates proliferation and survival through the Wnt cascade in vascular smooth muscle cells. American Journal of Physiology. Heart and Circulatory Physiology, 287, H2376–2383.

    PubMed  Article  CAS  Google Scholar 

  8. Basi, D. L., Adhikari, N., Mariash, A., Li, Q., Kao, E., Mullegama, S. V., et al. (2007). Femoral artery neointimal hyperplasia is reduced after wire injury in Ref-1+/− mice. American Journal of Physiology. Heart and Circulatory Physiology, 292, H516–521.

    PubMed  Article  CAS  Google Scholar 

  9. Tanaka, K., Sata, M., Hirata, Y., & Nagai, R. (2003). Diverse contribution of bone marrow cells to neointimal hyperplasia after mechanical vascular injuries. Circulation Research, 93, 783–790.

    PubMed  Article  CAS  Google Scholar 

  10. Ledin, J., Staatz, W., Li, J. P., Götte, M., Selleck, S., Kjellén, L., et al. (2004). Heparan sulfate structure in mice with genetically modified heparan sulfate production. Journal of Biological Chemistry, 279, 42732–42741.

    PubMed  Article  CAS  Google Scholar 

  11. Forsberg, E., & Kjellen, L. (2001). Heparan sulfate: Lessons from knockout mice. Journal of Clinical Investigation, 108, 175–180.

    PubMed  CAS  Google Scholar 

  12. Kjellen, L. (2003). Glucosaminyl N-deacetylase/N-sulphotransferases in heparan sulphate biosynthesis and biology. Biochemical Society Transactions, 31, 340–342.

    PubMed  Article  CAS  Google Scholar 

  13. Grobe, K., Ledin, J., Ringvall, M., Holmborn, K., Forsberg, E., Esko, J. D., et al. (2002). Heparan sulfate and development: differential roles of the N-acetylglucosamine N-deacetylase/N-sulfotransferase isozymes. Biochimica et Biophysica Acta, 1573, 209–15.

    PubMed  CAS  Google Scholar 

  14. Kreuger, J., Spillmann, D., Li, J.-P., & Lindahl, U. (2006). Interactions between heparan sulfate and proteins: The concept of specificity. Journal of Biological Chemistry, 174, 323–327.

    CAS  Google Scholar 

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Correspondence to Jennifer L. Hall.

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Adhikari, N., Rusch, M., Mariash, A. et al. Alterations in Heparan Sulfate in the Vessel in Response to Vascular Injury in the Mouse. J. of Cardiovasc. Trans. Res. 1, 236–240 (2008). https://doi.org/10.1007/s12265-008-9047-8

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  • DOI: https://doi.org/10.1007/s12265-008-9047-8

Keywords

  • Heparan Sulfate
  • Vascular Injury
  • N-Deacetylase-N-Sulfotransferase
  • Exostoses
  • O-Sulfotransferase