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Research Article
TNF receptors regulate vascular homeostasis in zebrafish through a caspase-8, caspase-2 and P53 apoptotic program that bypasses caspase-3
Raquel Espín, Francisco J. Roca, Sergio Candel, María P. Sepulcre, Juan M. González-Rosa, Francisca Alcaraz-Pérez, José Meseguer, María L. Cayuela, Nadia Mercader, Victoriano Mulero
Disease Models & Mechanisms 2013 6: 383-396; doi: 10.1242/dmm.010249
Raquel Espín
1Departmento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, 30100 Murcia, Spain
2Instituto Murciano de Investigación Biosanitaria (IMIB), 30100 Murcia, Spain
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Francisco J. Roca
1Departmento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, 30100 Murcia, Spain
3Department of Microbiology, University of Washington, Seattle, WA 98195, USA
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Sergio Candel
1Departmento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, 30100 Murcia, Spain
2Instituto Murciano de Investigación Biosanitaria (IMIB), 30100 Murcia, Spain
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María P. Sepulcre
1Departmento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, 30100 Murcia, Spain
2Instituto Murciano de Investigación Biosanitaria (IMIB), 30100 Murcia, Spain
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Juan M. González-Rosa
4Departamento de Biología del Desarrollo Cardiovascular, Centro Nacional de Investigaciones Cardiovasculares, Melchor Fernández Almagro 3, 28029 Madrid, Spain
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Francisca Alcaraz-Pérez
1Departmento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, 30100 Murcia, Spain
2Instituto Murciano de Investigación Biosanitaria (IMIB), 30100 Murcia, Spain
5Telomerase, Cancer and Aging Group, Research Unit, Department of Surgery, University Hospital ‘Virgen de la Arrixaca’, 30120 Murcia, Spain
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José Meseguer
1Departmento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, 30100 Murcia, Spain
2Instituto Murciano de Investigación Biosanitaria (IMIB), 30100 Murcia, Spain
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María L. Cayuela
2Instituto Murciano de Investigación Biosanitaria (IMIB), 30100 Murcia, Spain
5Telomerase, Cancer and Aging Group, Research Unit, Department of Surgery, University Hospital ‘Virgen de la Arrixaca’, 30120 Murcia, Spain
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Nadia Mercader
4Departamento de Biología del Desarrollo Cardiovascular, Centro Nacional de Investigaciones Cardiovasculares, Melchor Fernández Almagro 3, 28029 Madrid, Spain
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Victoriano Mulero
1Departmento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, 30100 Murcia, Spain
2Instituto Murciano de Investigación Biosanitaria (IMIB), 30100 Murcia, Spain
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SUMMARY

Although it is known that tumor necrosis factor receptor (TNFR) signaling plays a crucial role in vascular integrity and homeostasis, the contribution of each receptor to these processes and the signaling pathway involved are still largely unknown. Here, we show that targeted gene knockdown of TNFRSF1B in zebrafish embryos results in the induction of a caspase-8, caspase-2 and P53-dependent apoptotic program in endothelial cells that bypasses caspase-3. Furthermore, the simultaneous depletion of TNFRSF1A or the activation of NF-κB rescue endothelial cell apoptosis, indicating that a signaling balance between both TNFRs is required for endothelial cell integrity. In endothelial cells, TNFRSF1A signals apoptosis through caspase-8, whereas TNFRSF1B signals survival via NF-κB. Similarly, TNFα promotes the apoptosis of human endothelial cells through TNFRSF1A and triggers caspase-2 and P53 activation. We have identified an evolutionarily conserved apoptotic pathway involved in vascular homeostasis that provides new therapeutic targets for the control of inflammation- and tumor-driven angiogenesis.

Footnotes

  • COMPETING INTERESTS: The authors declare that they do not have any competing or financial interests.

  • AUTHOR CONTRIBUTIONS: F.J.R., R.E. and V.M. designed the research; F.J.R., R.E., S.C., M.P.S., J.M.G.-R., N.M. and F.A.-P., performed research; F.J.R., R.E., S.C., M.P.S., J.M.G.-R., N.M., F.A.-P., M.L.C., J.M. and V.M. analyzed data; and F.J.R. and V.M. wrote the paper with contributions from other authors.

  • SUPPLEMENTARY MATERIAL: Supplementary material for this article is available at http://dmm.biologists.Org/lookup/suppl/doi:10.1242/dmm.010249/-/DC1

  • Received May 25, 2012.
  • Accepted August 18, 2012.
  • © 2013. Published by The Company of Biologists Ltd

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Share Alike License (http://creativecommons.org/licenses/by-nc-sa/3.0), which permits unrestricted non-commercial use, distribution and reproduction in any medium provided that the original work is properly cited and all further distributions of the work or adaptation are subject to the same Creative Commons License terms.

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Research Article
TNF receptors regulate vascular homeostasis in zebrafish through a caspase-8, caspase-2 and P53 apoptotic program that bypasses caspase-3
Raquel Espín, Francisco J. Roca, Sergio Candel, María P. Sepulcre, Juan M. González-Rosa, Francisca Alcaraz-Pérez, José Meseguer, María L. Cayuela, Nadia Mercader, Victoriano Mulero
Disease Models & Mechanisms 2013 6: 383-396; doi: 10.1242/dmm.010249
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Research Article
TNF receptors regulate vascular homeostasis in zebrafish through a caspase-8, caspase-2 and P53 apoptotic program that bypasses caspase-3
Raquel Espín, Francisco J. Roca, Sergio Candel, María P. Sepulcre, Juan M. González-Rosa, Francisca Alcaraz-Pérez, José Meseguer, María L. Cayuela, Nadia Mercader, Victoriano Mulero
Disease Models & Mechanisms 2013 6: 383-396; doi: 10.1242/dmm.010249

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