Skip to main content
SpringerLink
Log in

Sildenafil citrate induces migration of mouse aortic endothelial cells and proteinase secretion

  • Published:
Biotechnology and Bioprocess Engineering Aims and scope Submit manuscript

Abstract

Vascular endothelial cells release proteinases that degrade the extracellular matrix (ECM), thus enabling cell migration during angiogenesis and vasculogenesis. Sildenafil citrate stimulates the nitric oxide-cyclic guanosine monophosphate pathway through inhibition of phosphodiesterase type V (PDE5). In this report, we examined the mechanisms underlying sildenafil citrate-induced cell migration using cultured mouse aortic endothelial cells (MAECs). Sildenafil citrate induced migration and proteinase secretion by murine endothelial cells. Sildenafil citrate induced the secretion of matrix metalloproteinase-2 (MMP-2) and MMP-9, which is inhibited by NF-κB inhibitors. Sildenafil citrate also induced the secretion of plasmin, which is inhibited by Pl 3′-kinase inhibitors. It is suggested that sildenafil citrate-induced migrating activity in endothelial cells may be accomplished by increased secretion of proteinases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Sanchez, L. S., S. M. de la Monte, G. Filippov, R. C. Jones, W. M. Zapol, and K. D. Bloch (1998) Cyclic-GMP-binding, cyclic-GMP-specific phosphodiesterase (PDE5) gene expression is regulated during rat pulmonary development.Pediatr. Res. 43: 163–168.

    Article  CAS  Google Scholar 

  2. Lucas, K. A., G. M. Pitari, S. Kazerounian, I. Ruiz-Stewart, J. Park, S. Schultz, K. P. Chepenik, and S. A. Waldman (2000) Guanylyl cyclase and signaling by cyclic GMP.Pharmacol. Rev. 52: 375–414.

    CAS  Google Scholar 

  3. Goldstein, I., T. F. Lue, H. Padma-Nathan, R. C. Rosen, W. D. Steers, and P. A. Wicker (1998) Oral sildenafil in the treatment of erectile dysfunction.N. Engl. J. Med. 338: 1397–1404.

    Article  CAS  Google Scholar 

  4. Wallis, R. M., J. D. Corbin, S. H. Francis, and P. Ellis (1999) Tissue distribution of phosphodiesterase families and the effects of sildenafil on tissue cyclic nucleotides, platelet function, and the contractile response of trabeculae carneae and aortic ringsin vitro.Am. J. Cardiol. 83: 3–12.

    Article  Google Scholar 

  5. Risau, W. (1997) Mechanisms of angiogenesis.Nature 386: 671–674.

    Article  CAS  Google Scholar 

  6. Folkman, J. and Y. Shing (1992) Angiogenesis.J. Biol. Chem. 267: 10931–10934.

    CAS  Google Scholar 

  7. Brooks, P. C., S. Silletti, T. L. von Schalscha, M. Friedlander, and D. A. Cheresh (1998) Disruption of angiogenesis by PEX, a noncatalytic metalloproteinase fragment with integrin binding activity.Cell 92: 391–400.

    Article  CAS  Google Scholar 

  8. Lee, J. B., J. S. Bae, J. H. Choi, J. H. Ham, Y. K. Min, H. M. Yang, T. Othman, and K. Shimizu (2004) Anticancer efficacies of doxorubicin, verapamil and quercetin on FM3A cells under hyperthermic temperature.Biotechnol. Bioprocess Eng. 9: 261–266.

    Article  CAS  Google Scholar 

  9. Frederick, J. and J. F. Woessner, Jr. (1988) The matrix metalloproteinase family. pp. 1–14. In: W. C. Parks and R. P. Mecham (eds.)Matrix Metalloproteinases. Academic Press, London, UK.

    Google Scholar 

  10. Stetler-Stevenson, W. G. (1999) Matrix metalloproteinases in angiogenesis: a moving target for therapeutic intervention.J. Clin. Invest. 103: 1237–1241.

    Article  CAS  Google Scholar 

  11. Nagase, H. (1997) Activation mechanisms of matrix metalloproteinases.Biol. Chem. 378: 151–160.

    CAS  Google Scholar 

  12. Haris, S. G. and M. L. Shuler (2003) Growth of endothelial cells on microfabricated silicon nitride membranes for anin vivo model of the blood-brain barrier.Biotechnol. Bioprocess Eng. 8: 246–251.

    Article  Google Scholar 

  13. Oh, I. S. and H. G. Kim (2004) Vascular endothelial growth factor upregulates follistatin in human umbilical vein endothelial cells.Biotechnol. Bioprocess Eng. 9: 201–206.

    Article  CAS  Google Scholar 

  14. Oh, I. S., J. W. Han, and H. G. Kim (2005) Water extracts ofAralia elata root bark enhances migration and matrix metalloproteinases secretion in porcine coronary artery endothelial cells.Biotechnol. Bioprocess Eng. 10: 372–377.

    Article  CAS  Google Scholar 

  15. Rosen, E. M., L. Meromsky, E. Setter, D. W. Vinter, and I. D. Goldberg (1990) Quantitation of cytokine-stimulated migration of endothelium and epithelium by a new assay using microcarrier beads.Exp. Cell Res. 186: 22–31.

    Article  CAS  Google Scholar 

  16. Kleiner, D. E., I. M. K. Margulis, and W. G. Stetler-Stevenson (1998) Proteinase assay/zymography. pp. 5A7.1–5A7.8. In: A. Doyle, J. B. Griffiths, and D. G. Newell (eds.)Cell and Tissue Culture: Laboratory Procedures, John Wiley and Sons, Sussex, UK.

    Google Scholar 

  17. Lee, Y. M., H. Kim, E. K. Hong, B. H. Kang, and S. J. Kim (2000) Water extract of 1∶1 mixture ofPhellodendron cortex andAralia cortex has inhibitory effects on oxidative stress in kidney of diabetic rats.J. Ethnopharmacol. 73: 429–436.

    Article  CAS  Google Scholar 

  18. Hiraoka, N., E. Allen, I. J. Apel, M. R. Gyetko, and S. J. Weiss (1998) Matrix metalloproteinases regulate neovascularization by acting as pericellular fibrinolysins.Cell 95: 365–377.

    Article  CAS  Google Scholar 

  19. Brown, M. D. and O. Hudlicka (2003) Modulation of physiological angiogenesis in skeletal muscle by mechanical forces involvement of VEGF and metalloproteinases.Angiogenesis 6: 1–14.

    Article  CAS  Google Scholar 

  20. DeClerck, Y. A., T. D. Yean, H. S. Lu, J. Ting, and K. E. Langley (1991) Inhibition of autoproteolytic activation of interstitial procollagenase by recombinant metalloproteinase inhibitor MI/TIMP-2.J. Biol. Chem. 266: 3893–3899.

    CAS  Google Scholar 

  21. Ward, R. V., R. M. Hembry, J. J. Reynolds, and G. Murphy (1991) The purification of tissue inhibitor of metalloproteinases-2 from its 72 kDa progelatinase complex. Demonstration of the biochemical similarities of tissue inhibitor of metalloproteinases-2 and tissue inhibitor of metalloproteinases-1.Biochem. J. 278: 179–187.

    CAS  Google Scholar 

  22. Hajjar, K. A. (1995) Changing concepts in fibrinolysis.Curr. Opin. Hematol. 2: 345–350.

    Article  CAS  Google Scholar 

  23. Lijnen, H. R. (2001) Plasmin and matrix metalloproteinases in vascular remodeling.Thromb. Haemost. 86: 324–333.

    CAS  Google Scholar 

  24. He, C. S., S. M. Wilhelm, A. P. Pentland, B. L. Marmer, G. A. Grant, A. Z. Eisen, and G. I. Goldberg (1989) Tissue cooperation in a proteolytic cascade activating human interstitial collagenase.Proc. Natl. Acad. Sci. USA 86: 2632–2636.

    Article  CAS  Google Scholar 

  25. Baramova, E. N., K. Bajou, A. Remacle, C. L’Hoir, H. W. Krell, U. H. Weidle, A. Noel, and J. M. Foidart (1997) Involvement of PA/plasmin system in the processing of pro-MMP-9 and in the second step of pro-MMP-2 activation.FEBS Lett. 405: 157–162.

    Article  CAS  Google Scholar 

  26. Kim, H. G. and G. Y. Koh (2000) Lipopolysaccharide activates matrix metalloproteinase-2 in endothelial cells through an NF-κB-dependent pathway.Biochem. Biophys. Res. Commun. 269: 401–405.

    Article  CAS  Google Scholar 

  27. Fini, E. M., J. R. Cook, R. Mohan, and C. E. Brinckerhoff (1988) Regulation of matrix metalloproteinase gene expression. pp. 299–356. In: W. C. Parks and R. P. Mecham (eds.),Matrix Metalloproteinase. Academic Press, London, UK.

    Google Scholar 

  28. Folkman, J. and P. A. D’Amore (1996) Blood vessel formation: what is its molecular basis?.Cell 87: 1153–1155.

    Article  CAS  Google Scholar 

  29. Veikkola, T. and K. Alitalo (1999) VEGFs, receptors and angiogenesis.Semin. Cancer Biol. 9: 211–220.

    Article  CAS  Google Scholar 

  30. Hanahan, D. (1997) Signaling vascular morphogenesis and maintenance.Science 277: 48–50.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Physical Education, Yonsei University, 120-749, Seoul, Korea

    Young Il Kim

  2. Division of Biological Sciences, Research Center of Bioactive Materials, Chonbuk National University, 561-756, Jeonju, Korea

    In Suk Oh, Seung Moon Park & Hwan Gyu Kim

Authors
  1. Young Il Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. In Suk Oh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Seung Moon Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hwan Gyu Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hwan Gyu Kim.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kim, Y.I., Oh, I.S., Park, S.M. et al. Sildenafil citrate induces migration of mouse aortic endothelial cells and proteinase secretion. Biotechnol. Bioprocess Eng. 11, 402–407 (2006). https://doi.org/10.1007/BF02932306

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02932306

Keywords

Search

Navigation