Birc2 (cIap1) regulates endothelial cell integrity and blood vessel homeostasis.
Integrity of the blood vessel wall is essential for vascular homeostasis and organ function. A dynamic balance between endothelial cell survival and apoptosis contributes to this integrity during vascular development and pathological angiogenesis. The genetic and molecular mechanisms regulating these processes in vivo are still largely unknown. Here, we show that Birc2 (also known as cIap1) is essential for maintaining endothelial cell survival and blood vessel homeostasis during vascular development. Using a forward-genetic approach, we identified a zebrafish null mutant for birc2, which shows severe hemorrhage and vascular regression due to endothelial cell integrity defects and apoptosis. Using genetic and molecular approaches, we show that Birc2 positively regulates the formation of the TNF receptor complex I in endothelial cells, thereby promoting NF-kappaB activation and maintaining vessel integrity and stabilization. In the absence of Birc2, a caspase-8-dependent apoptotic program takes place that leads to vessel regression. Our findings identify Birc2 and TNF signaling components as critical regulators of vascular integrity and endothelial cell survival, thereby providing an additional target pathway for the control of angiogenesis and blood vessel homeostasis during embryogenesis, regeneration and tumorigenesis.
Santoro
Massimo M
MM
Department of Biochemistry and Biophysics, Programs in Developmental Biology, Genetics and Human Genetics, and Cardiovascular Research Institute, University of California San Francisco, San Francisco, California 94158, USA. massimo.santoro@ucsf.edu
Samuel
Temesgen
T
Mitchell
Tracy
T
Reed
John C
JC
Stainier
Didier Y R
DY
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology* / Q000378:metabolism; D006706:Homeostasis; D015151:Immunoblotting; D017403:In Situ Hybridization; D051034:Inhibitor of Apoptosis Proteins / Q000502:physiology*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D019076:Transgenes / Q000502:physiology; D014471:Umbilical Veins / Q000166:cytology / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000502:physiology*
D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; D047992:TNF Receptor-Associated Factor 2; D029961:Zebrafish Proteins; D020169:Caspases