Selective inhibition of vascular endothelial growth factor-mediated angiogenesis by cyclosporin A: Roles of the nuclear factor of activated T cells and cyclooxygenase 2

Gabriela L. Hernández, Olga V. Volpert, Miguel A. Íñiguez, Elisa Lorenzo, Sara Martínez-Martínez, Raquel Grau, Manuel Fresno, Juan Miguel Redondo*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

366 Scopus citations

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 E2. 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.

Original languageEnglish (US)
Pages (from-to)607-620
Number of pages14
JournalJournal of Experimental Medicine
Volume193
Issue number5
DOIs
StatePublished - Mar 5 2001

Keywords

  • Angiogenesis
  • Cyclooxygenase
  • Cyclosporin A
  • NFAT
  • VEGF

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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