Article

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

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.
Nature Genetics (impact factor: 35.53). 12/2007; 39(11):1397-402. DOI:10.1038/ng.2007.8 pp.1397-402
Source: PubMed

ABSTRACT 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.

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Keywords

additional target pathway
 
blood vessel homeostasis
 
blood vessel wall
 
caspase-8-dependent apoptotic program
 
critical regulators
 
endothelial cell integrity defects
 
endothelial cell survival
 
endothelial cells
 
molecular mechanisms regulating
 
NF-kappaB activation
 
organ function
 
pathological angiogenesis
 
TNF receptor complex
 
TNF signaling components
 
vascular development
 
vascular homeostasis
 
vascular integrity
 
vascular regression
 
vessel integrity
 
zebrafish null mutant