Abstract
Signaling events that regulate central nervous system (CNS) angiogenesis and blood-brain barrier (BBB) formation are only beginning to be elucidated. By evaluating the gene expression profile of mouse vasculature, we identified DR6/TNFRSF21 and TROY/TNFRSF19 as regulators of CNS-specific angiogenesis in both zebrafish and mice. Furthermore, these two death receptors interact both genetically and physically and are required for vascular endothelial growth factor (VEGF)-mediated JNK activation and subsequent human brain endothelial sprouting in vitro. Increasing beta-catenin levels in brain endothelium upregulate DR6 and TROY, indicating that these death receptors are downstream target genes of Wnt/beta-catenin signaling, which has been shown to be required for BBB development. These findings define a role for death receptors DR6 and TROY in CNS-specific vascular development.
Copyright © 2012 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Biomarkers / metabolism
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Blood-Brain Barrier / metabolism*
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Blotting, Western
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Cell Communication
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Cells, Cultured
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Central Nervous System / blood supply*
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Central Nervous System / metabolism*
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Embryo, Mammalian / cytology
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Embryo, Mammalian / metabolism
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Endothelium, Vascular / cytology
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Endothelium, Vascular / metabolism
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Gene Expression Profiling
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Gene Expression Regulation, Developmental
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Humans
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Immunoprecipitation
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MAP Kinase Kinase 4 / antagonists & inhibitors
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MAP Kinase Kinase 4 / genetics
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MAP Kinase Kinase 4 / metabolism
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Mice
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Neovascularization, Physiologic*
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Oligonucleotide Array Sequence Analysis
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RNA, Messenger / genetics
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RNA, Small Interfering / genetics
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Real-Time Polymerase Chain Reaction
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Receptors, Tumor Necrosis Factor / genetics
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Receptors, Tumor Necrosis Factor / metabolism*
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Signal Transduction
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism
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Zebrafish / growth & development
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Zebrafish / metabolism
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beta Catenin / genetics
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beta Catenin / metabolism
Substances
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Biomarkers
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RNA, Messenger
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RNA, Small Interfering
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Receptors, Tumor Necrosis Factor
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Tnfrsf19 protein, mouse
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Tnfrsf21 protein, mouse
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Vascular Endothelial Growth Factor A
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beta Catenin
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MAP Kinase Kinase 4