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Original Article

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

^a Centro de Biología Molecular "Severo Ochoa, " Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid, Facultad de Ciencias, E-28049 Madrid, Spain
^b Department of Urology, Robert H. Lurie C. Cancer Center, Chicago, Illinois 60611
Centro de Biología Molecular "Severo Ochoa," Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid, Facultad de Ciencias, E-28049 Madrid, Spain.34-91-397-808734-91-397-8270

jmredondo{at}cbm.uam.es

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.

Key Words: NFAT • cyclosporin A • VEGF • cyclooxygenase • angiogenesis

© 2001 The Rockefeller University Press

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