Selective Inhibition of Vascular Endothelial Growth Factor–mediated Angiogenesis by Cyclosporin A: Roles of the Nuclear Factor of Activated T Cells and Cyclooxygenase 2
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.This work was supported by grant PM99-0116 from Ministerio de Educación y Cultura (MEC-DGES) of Spain (to J.M. Redondo) and grants FEDER 1FD97-0514-CO2-01 and FEDER FD97-0275 from MEC-DGES and the European Community to J.M. Redondo and M. Fresno, respectively. G.L. Hernández was supported by grants from Consejo Superior de Investigaciones Científicas y Tecnológicas (CONICET) of Argentina and Comunidad Autónoma de Madrid grant 8.3/0024/2000, and M. Fresno by grant PM97-0130, O. Volpert by American Heart Association grant AHA SDG 0030023N, and S. Martínez-Martínez by grant 8.3/19/1998 from the Comunidad Autónoma de Madrid. The Centro de Biología Molecular "Severo Ochoa" is supported by a grant from the Fundación Ramón ArecesPeer reviewe
