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Selective Inhibition of Vascular Endothelial Growth Factor–Mediated Angiogenesis by Cyclosporin a

Selective Inhibition of Vascular Endothelial Growth Factor–Mediated Angiogenesis by Cyclosporin a Cyclosporin A (CsA) is an immunosuppressive drug that inhibits the activity of transcription factors of the nuclear factor of activated T cells (NFAT) family, interfering with the induction of cytokines and other inducible genes required for the immune response. Here we show that CsA inhibits migration of primary endothelial cells and angiogenesis induced by vascular endothelial growth factor (VEGF); this effect appears to be mediated through the inhibition of cyclooxygenase (Cox)-2, the transcription of which is activated by VEGF in primary endothelial cells. Consistent with this, we show that the induction of Cox-2 gene expression by VEGF requires NFAT activation. Most important, the CsA-mediated inhibition of angiogenesis both in vitro and in vivo was comparable to the Cox-2 inhibitor NS-398, and reversed by prostaglandin E 2 . Furthermore, the in vivo corneal angiogenesis induced by VEGF, but not by basic fibroblast growth factor, was selectively inhibited in mice treated with CsA systemically. These findings involve NFAT in the regulation of Cox-2 in endothelial cells, point to a role for this transcription factor in angiogenesis, and may provide a novel mechanism underlying the beneficial effects of CsA in angiogenesis-related diseases such as rheumatoid arthritis and psoriasis. NFAT cyclosporin A VEGF cyclooxygenase angiogenesis Footnotes Abbreviations used in this paper: AA, arachidonic acid; bFGF, basic fibroblast growth factor; Cox, cyclooxygenase; CRE, cAMP response element; CsA, cyclosporin A; EMSA, electrophoretic mobility shift assay; HUVEC, human umbilical vein endothelial cell; NFAT, nuclear factor of activated T cells; NSAID, nonsteroidal antiinflammatory drug; PG, prostaglandin; PA, plasminogen activator; VEGF, vascular endothelial growth factor. Submitted: 1 August 2000 Revision requested 6 December 2000 Accepted: 23 January 2001 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Experimental Medicine Rockefeller University Press

Selective Inhibition of Vascular Endothelial Growth Factor–Mediated Angiogenesis by Cyclosporin a

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Publisher
Rockefeller University Press
Copyright
© 2001 The Rockefeller University Press
ISSN
0022-1007
eISSN
1540-9538
DOI
10.1084/jem.193.5.607
Publisher site
See Article on Publisher Site

Abstract

Cyclosporin A (CsA) is an immunosuppressive drug that inhibits the activity of transcription factors of the nuclear factor of activated T cells (NFAT) family, interfering with the induction of cytokines and other inducible genes required for the immune response. Here we show that CsA inhibits migration of primary endothelial cells and angiogenesis induced by vascular endothelial growth factor (VEGF); this effect appears to be mediated through the inhibition of cyclooxygenase (Cox)-2, the transcription of which is activated by VEGF in primary endothelial cells. Consistent with this, we show that the induction of Cox-2 gene expression by VEGF requires NFAT activation. Most important, the CsA-mediated inhibition of angiogenesis both in vitro and in vivo was comparable to the Cox-2 inhibitor NS-398, and reversed by prostaglandin E 2 . Furthermore, the in vivo corneal angiogenesis induced by VEGF, but not by basic fibroblast growth factor, was selectively inhibited in mice treated with CsA systemically. These findings involve NFAT in the regulation of Cox-2 in endothelial cells, point to a role for this transcription factor in angiogenesis, and may provide a novel mechanism underlying the beneficial effects of CsA in angiogenesis-related diseases such as rheumatoid arthritis and psoriasis. NFAT cyclosporin A VEGF cyclooxygenase angiogenesis Footnotes Abbreviations used in this paper: AA, arachidonic acid; bFGF, basic fibroblast growth factor; Cox, cyclooxygenase; CRE, cAMP response element; CsA, cyclosporin A; EMSA, electrophoretic mobility shift assay; HUVEC, human umbilical vein endothelial cell; NFAT, nuclear factor of activated T cells; NSAID, nonsteroidal antiinflammatory drug; PG, prostaglandin; PA, plasminogen activator; VEGF, vascular endothelial growth factor. Submitted: 1 August 2000 Revision requested 6 December 2000 Accepted: 23 January 2001

Journal

The Journal of Experimental Medicine – Rockefeller University Press

Published: Mar 5, 2001

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