Abstract
Tight regulation of the balance between apoptosis and survival is essential in angiogenesis. The ETS transcription factor Erg is required for endothelial tube formation in vitro. Inhibition of Erg expression in human umbilical vein endothelial cells (HUVECs), using antisense oligonucleotides, resulted in detachment of cell-cell contacts and increased cell death. Inhibition of Erg expression by antisense in HUVECs also lowered expression of the adhesion molecule vascular endothelial (VE)-cadherin, a key regulator of endothelial intercellular junctions and survival. Using chromatin immunoprecipitation, we showed that Erg binds to the VE-cadherin promoter. Furthermore, Erg was found to enhance VE-cadherin promoter activity in a transactivation assay. Apoptosis induced by inhibition of Erg was partly rescued by overexpression of VE-cadherin-GFP, suggesting that VE-cadherin is involved in the Erg-dependent survival signals. To show the role of Erg in angiogenesis in vivo, we used siRNA against Erg in a Matrigel plug model. Erg inhibition resulted in a significant decrease in vascularization, with increase in caspase-positive endothelial cells (ECs). These results identify a new pathway regulating angiogenesis and endothelial survival, via the transcription factor Erg and the adhesion molecule VE-cadherin.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antigens, CD / biosynthesis*
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Antigens, CD / genetics
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Apoptosis / drug effects
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Apoptosis / physiology*
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Cadherins / biosynthesis*
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Cadherins / genetics
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Caspases / genetics
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Caspases / metabolism
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Cell Adhesion / drug effects
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Cell Adhesion / physiology
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Cell Survival / drug effects
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Cell Survival / physiology
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Cells, Cultured
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Endothelial Cells / cytology
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Endothelial Cells / metabolism*
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / physiology*
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Humans
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Intercellular Junctions / drug effects
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Intercellular Junctions / genetics
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Intercellular Junctions / metabolism
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Neovascularization, Physiologic / drug effects
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Neovascularization, Physiologic / physiology*
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Oligonucleotides, Antisense / genetics
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Oligonucleotides, Antisense / pharmacology
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Promoter Regions, Genetic / physiology
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Protein Binding / drug effects
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Protein Binding / physiology
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RNA, Small Interfering / genetics
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RNA, Small Interfering / pharmacology
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Trans-Activators / antagonists & inhibitors
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Transcriptional Regulator ERG
Substances
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Antigens, CD
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Cadherins
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DNA-Binding Proteins
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ERG protein, human
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Oligonucleotides, Antisense
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RNA, Small Interfering
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Trans-Activators
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Transcriptional Regulator ERG
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cadherin 5
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Caspases