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Birc2 (cIap1) regulates endothelial cell integrity and blood vessel homeostasis

Abstract

Integrity of the blood vessel wall is essential for vascular homeostasis and organ function1,2. A dynamic balance between endothelial cell survival and apoptosis contributes to this integrity during vascular development and pathological angiogenesis3,4,5,6. 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-κB 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.

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Figure 1: Vascular integrity and endothelial survival are defective in tom mutants.
Figure 2: tom encodes Birc2.
Figure 3: Birc2 regulates TNFR-TRAF2 signaling and death receptor–mediated caspase-8 activation in endothelial cells.
Figure 4: NF-κB activation is regulated by Birc2 in endothelial cells and regulates vascular homeostasis in zebrafish embryos.

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Acknowledgements

We would like to thank members of the Stainier laboratory for invaluable support and E. Kratz and P. Eimon for discussion and reagents. Support for this research came from a Human Frontier Science Program Fellowship (M.M.S.), Cardiovascular Research Institute National Institutes of Health Training Grant (T.M.) and grants from the US National Institutes of Health (AG-15402 (J.C.R.); HL-54737 (D.Y.R.S.)), American Heart Association and Packard Foundation (D.Y.R.S.).

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Correspondence to Massimo M Santoro or Didier Y R Stainier.

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Santoro, M., Samuel, T., Mitchell, T. et al. Birc2 (cIap1) regulates endothelial cell integrity and blood vessel homeostasis. Nat Genet 39, 1397–1402 (2007). https://doi.org/10.1038/ng.2007.8

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