Skip to main content
  • Short Communication
  • Published:

ZFAT is essential for endothelial cell assembly and the branch point formation of capillary-like structures in an angiogenesis model

Abstract

ZFAT, originally identified as a susceptibility gene for autoimmune thyroid disease, encodes a transcriptional regulator with one AT-hook and 18 C2H2-type zinc-finger domains. It is highly conserved among species. Here, we demonstrate that ZFAT is clearly expressed in human umbilical vein endothelial cells (HUVECs). Furthermore, we show that endothelial cell assembly and the branch point formation of capillary-like structures in HUVECs is impaired by the reduction of ZFAT expression through the use of ZFAT-miRNAs, whereas differences in cell proliferation or apoptotic features were not observed after the reduction in ZFAT expression. These results suggest that ZFAT may have critical roles in the capillary-like network formation that is involved in vascular remodeling. Elucidating the ZFAT-mediated transcriptional network will lead to a better understanding of the molecular mechanisms of angiogenesis.

Abbreviations

C2H2 :

Cys2-His2

HUVECs:

human umbilical vein endothelial cells

miRNA:

microRNA

ZFAT:

zinc-finger gene in autoimmune thyroid disease susceptibility region

References

  1. Shirasawa, S., Harada, H., Furugaki, K., Akamizu, T., Ishikawa, N., Ito, K., Ito, K., Tamai, H., Kuma, K., Kubota, S., Hiratani, H., Tsuchiya, T., Baba, I., Ishikawa, M., Tanaka, M., Sakai, K., Aoki, M., Yamamoto, K. and Sasazuki, T. SNPs in the promoter of a B cell-specific antisense transcript, SAS-ZFAT, determine susceptibility to autoimmune thyroid disease. Hum. Mol. Genet. 13 (2004) 2221–2231.

    Article  CAS  PubMed  Google Scholar 

  2. Koyanagi, M., Nakabayashi, K., Fujimoto, T., Gu, N., Baba, I., Takashima, Y., Doi, K., Harada, H., Kato, N., Sasazuki, T. and Shirasawa, S. ZFAT expression in B and T lymphocytes and identification of ZFAT-regulated genes. Genomics 91 (2008) 451–457.

    Article  CAS  PubMed  Google Scholar 

  3. Fujimoto, T., Doi, K., Koyanagi, M., Tsunoda, T., Takashima, Y., Yoshida, Y., Sasazuki, T. and Shirasawa, S. ZFAT is an antiapoptotic molecule and critical for cell survival in MOLT-4 cells. FEBS Lett. 583 (2009) 568–572.

    Article  CAS  PubMed  Google Scholar 

  4. Comabella, M., Craig, D.W., Morcillo-Suárez, C., Río, J., Navarro, A., Fernández, M., Martin, R. and Montalban X. Genome-wide scan of 500,000 single-nucleotide polymorphisms among responders and nonresponders to interferon beta therapy in multiple sclerosis. Arch. Neurol. 66 (2009) 972–978.

    Article  PubMed  Google Scholar 

  5. Takeuchi, F., Nabika, T., Isono, M., Katsuya, T., Sugiyama, T., Yamaguchi, S., Kobayashi, S., Yamori, Y., Ogihara, T. and Kato N. Evaluation of genetic loci influencing adult height in the Japanese population. J. Hum. Genet. 54 (2009) 749–752.

    Article  PubMed  Google Scholar 

  6. Cho, Y.S., Go, M.J., Kim, Y.J., Heo, J.Y., Oh, J.H., Ban, H.J., Yoon, D., Lee, M.H., Kim, D.J., Park, M., Cha, S.H., Kim, J.W., Han, B.G., Min, H., Ahn, Y., Park, M.S., Han, H.R., Jang, H.Y., Cho, E.Y., Lee, J.E., Cho, N.H., Shin, C., Park, T., Park, J.W., Lee, J.K., Cardon, L., Clarke, G., McCarthy, M.I., Lee, J.Y., Lee, J.K., Oh, B. and Kim, H.L. A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits. Nat. Genet. 41 (2009) 527–534.

    Article  CAS  PubMed  Google Scholar 

  7. Carmeliet, P. Mechanisms of angiogenesis and arteriogenesis. Nat. Med. 6 (2000) 389–395.

    Article  CAS  PubMed  Google Scholar 

  8. Gary H. Gibbons, and Victor J. Dzau. The Emerging Concept of Vascular Remodeling. N. Engl. J. Med. 330 (2000) 1431–1438.

    Google Scholar 

  9. Carmeliet, P. and Jain, R.K. Angiogenesis in cancer and other diseases. Nature 407 (2000) 249–257.

    Article  CAS  PubMed  Google Scholar 

  10. Carmeliet, P. Angiogenesis in life, disease and medicine. Nature 438 (2005) 932–936.

    Article  CAS  PubMed  Google Scholar 

  11. Mor, F., Quintana, F.J. and Cohen, I.R. Angiogenesis-inflammation crosstalk: vascular endothelial growth factor is secreted by activated T cells and induces Th1 polarization. J. Immunol. 172 (2004) 4618–4623.

    CAS  PubMed  Google Scholar 

  12. Serini, G., Ambrosi, D., Giraudo, E., Gamba, A., Preziosi, L. and Bussolino, F. Modeling the early stages of vascular network assembly. EMBO J. 22 (2003) 1771–1779.

    Article  CAS  PubMed  Google Scholar 

  13. Mizukami, Y., Kohgo, Y. and Chung, D.C. Hypoxia inducible factor-1 independent pathways in tumor angiogenesis. Clin. Cancer Res. 13 (2007) 5670–5674.

    Article  CAS  PubMed  Google Scholar 

  14. Moehler, T.M., Ho, A.D., Goldschmidt, H. and Barlogie, B. Angiogenesis in hematologic malignancies. Crit. Rev. Oncol. Hematol. 45 (2003) 227–244.

    Article  CAS  PubMed  Google Scholar 

  15. Kamei, M., Saunders, W.B., Bayless, K.J., Dye, L., Davis, G.E. and Weinstein, B.M. Endothelial tubes assemble from intracellular vacuoles in vivo. Nature 442 (2006) 453–456.

    Article  CAS  PubMed  Google Scholar 

  16. Merks, R.M., Brodsky, S.V., Goligorksy, M.S., Newman, S.A. and Glazier, J.A. Cell elongation is key to in silico replication of in vitro vasculogenesis and subsequent remodeling. Dev. Biol. 289 (2006) 44–54.

    Article  CAS  PubMed  Google Scholar 

  17. Sottile, J. Regulation of angiogenesis by extracellular matrix. Biochim. Biophys. Acta 1654 (2004) 13–22.

    CAS  PubMed  Google Scholar 

  18. Tammela, T., Zarkada, G., Wallgard, E., Murtomäki, A., Suchting, S., Wirzenius, M., Waltari, M., Hellström, M., Schomber, T., Peltonen, R., Freitas, C., Duarte, A., Isoniemi, H., Laakkonen, P., Christofori, G., Yla-Herttuala, S., Shibuya, M., Pytowski, B., Eichmann, A., Betsholtz, C. and Alitalo, K. Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature 454 (2008) 656–660.

    Article  CAS  PubMed  Google Scholar 

  19. Staton, C.A., Reed, M.W. and Brown, N.J. A critical analysis of current in vitro and in vivo angiogenesis assays. Int. J. Exp. Pathol. 90 (2009) 195–221.

    CAS  PubMed  Google Scholar 

  20. Tsunoda, T., Takashima, Y., Fujimoto, T., Koyanagi, M., Yoshida, Y., Doi, K., Tanaka, Y., Kuroki, M., Sasazuki, T. and Shirasawa, S. Three-dimensionally specific inhibition of DNA repair-related genes by activated KRAS in colon crypt model. Neoplasia 12 (2010) 397–404.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Senji Shirasawa.

Additional information

These authors contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yoshida, Y., Tsunoda, T., Takashima, Y. et al. ZFAT is essential for endothelial cell assembly and the branch point formation of capillary-like structures in an angiogenesis model. Cell Mol Biol Lett 15, 541–550 (2010). https://doi.org/10.2478/s11658-010-0028-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2478/s11658-010-0028-y

Key words