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 migrat...

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Autores: Hernández, Gabriela L., Volpert, Olga V., Íñiguez, Miguel Ángel, Lorenzo, Elisa, Martínez Martínez, Sara, Grau, Raquel, Fresno, Manuel, Redondo, Juan Miguel
Tipo de recurso: artículo
Fecha de publicación:2001
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/7722
Acceso en línea:http://hdl.handle.net/10261/7722
Access Level:acceso abierto
Palabra clave:NFAT
Cyclosporin A
VEGF
Cyclooxygenase 2
Angiogenesis
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spelling Selective Inhibition of Vascular Endothelial Growth Factor–mediated Angiogenesis by Cyclosporin A: Roles of the Nuclear Factor of Activated T Cells and Cyclooxygenase 2Hernández, Gabriela L.Volpert, Olga V.Íñiguez, Miguel ÁngelLorenzo, ElisaMartínez Martínez, SaraGrau, RaquelFresno, ManuelRedondo, Juan MiguelNFATCyclosporin AVEGFCyclooxygenase 2AngiogenesisCyclosporin 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 reviewedRockefeller University PressMinisterio de Educación y Cultura (España)European CommissionConsejo Nacional de Investigaciones Científicas y Técnicas (Argentina)Comunidad de MadridFundación Ramón Areces200820082001info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501570155 bytesapplication/pdfhttp://hdl.handle.net/10261/7722reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttp://www.jem.org/cgi/content/full/193/5/607info:eu-repo/semantics/openAccessoai:digital.csic.es:10261/77222026-05-22T06:33:51Z
dc.title.none.fl_str_mv Selective Inhibition of Vascular Endothelial Growth Factor–mediated Angiogenesis by Cyclosporin A: Roles of the Nuclear Factor of Activated T Cells and Cyclooxygenase 2
title Selective Inhibition of Vascular Endothelial Growth Factor–mediated Angiogenesis by Cyclosporin A: Roles of the Nuclear Factor of Activated T Cells and Cyclooxygenase 2
spellingShingle Selective Inhibition of Vascular Endothelial Growth Factor–mediated Angiogenesis by Cyclosporin A: Roles of the Nuclear Factor of Activated T Cells and Cyclooxygenase 2
Hernández, Gabriela L.
NFAT
Cyclosporin A
VEGF
Cyclooxygenase 2
Angiogenesis
title_short Selective Inhibition of Vascular Endothelial Growth Factor–mediated Angiogenesis by Cyclosporin A: Roles of the Nuclear Factor of Activated T Cells and Cyclooxygenase 2
title_full Selective Inhibition of Vascular Endothelial Growth Factor–mediated Angiogenesis by Cyclosporin A: Roles of the Nuclear Factor of Activated T Cells and Cyclooxygenase 2
title_fullStr Selective Inhibition of Vascular Endothelial Growth Factor–mediated Angiogenesis by Cyclosporin A: Roles of the Nuclear Factor of Activated T Cells and Cyclooxygenase 2
title_full_unstemmed Selective Inhibition of Vascular Endothelial Growth Factor–mediated Angiogenesis by Cyclosporin A: Roles of the Nuclear Factor of Activated T Cells and Cyclooxygenase 2
title_sort Selective Inhibition of Vascular Endothelial Growth Factor–mediated Angiogenesis by Cyclosporin A: Roles of the Nuclear Factor of Activated T Cells and Cyclooxygenase 2
dc.creator.none.fl_str_mv Hernández, Gabriela L.
Volpert, Olga V.
Íñiguez, Miguel Ángel
Lorenzo, Elisa
Martínez Martínez, Sara
Grau, Raquel
Fresno, Manuel
Redondo, Juan Miguel
author Hernández, Gabriela L.
author_facet Hernández, Gabriela L.
Volpert, Olga V.
Íñiguez, Miguel Ángel
Lorenzo, Elisa
Martínez Martínez, Sara
Grau, Raquel
Fresno, Manuel
Redondo, Juan Miguel
author_role author
author2 Volpert, Olga V.
Íñiguez, Miguel Ángel
Lorenzo, Elisa
Martínez Martínez, Sara
Grau, Raquel
Fresno, Manuel
Redondo, Juan Miguel
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Educación y Cultura (España)
European Commission
Consejo Nacional de Investigaciones Científicas y Técnicas (Argentina)
Comunidad de Madrid
Fundación Ramón Areces
dc.subject.none.fl_str_mv NFAT
Cyclosporin A
VEGF
Cyclooxygenase 2
Angiogenesis
topic NFAT
Cyclosporin A
VEGF
Cyclooxygenase 2
Angiogenesis
description 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.
publishDate 2001
dc.date.none.fl_str_mv 2001
2008
2008
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/7722
url http://hdl.handle.net/10261/7722
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv http://www.jem.org/cgi/content/full/193/5/607
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 570155 bytes
application/pdf
dc.publisher.none.fl_str_mv Rockefeller University Press
publisher.none.fl_str_mv Rockefeller University Press
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.81155

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