title: TNF receptors regulate vascular homeostasis in zebrafish through a caspase-8, caspase-2 and P53 apoptotic program that bypasses caspase-3.
abstract: 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.
authors.affiliation: Departmento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, 30100 Murcia, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Espín
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Roca
authors.forename: Sergio
authors.initials: S
authors.lastname: Candel
authors.forename: María P
authors.initials: MP
authors.lastname: Sepulcre
authors.forename: Juan M
authors.initials: JM
authors.lastname: González-Rosa
authors.forename: Francisca
authors.initials: F
authors.lastname: Alcaraz-Pérez
authors.forename: José
authors.initials: J
authors.lastname: Meseguer
authors.forename: María L
authors.initials: ML
authors.lastname: Cayuela
authors.forename: Nadia
authors.initials: N
authors.lastname: Mercader
authors.forename: Victoriano
authors.initials: V
authors.lastname: Mulero
mesh_terms: D000818:Animals; D017209:Apoptosis; D001775:Blood Circulation; D001808:Blood Vessels / Q000378:metabolism*; D053143:Caspase 2 / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D020169:Caspases / Q000378:metabolism*; D017124:Conserved Sequence; D053938:DNA Fragmentation; D004625:Embryo, Nonmammalian / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000201:enzymology; D019143:Evolution, Molecular; D017353:Gene Deletion; D006706:Homeostasis; D006801:Humans; D008954:Models, Biological; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology / Q000378:metabolism*
chemical_list: D047888:Receptors, Tumor Necrosis Factor, Type I; D016159:Tumor Suppressor Protein p53; D053143:Caspase 2; D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases