Abstract
Suppression of tumor growth by inhibition of ErbB receptor signaling is well documented. However, relatively little is known about the ErbB signaling system in the regulation of angiogenesis, a process necessary for tumor growth. We have previously shown that heparin-binding EGF-like growth factor (HB-EGF) is expressed by vascular endothelial cells (EC) and promotes endothelial recruitment of vascular smooth muscle cells (SMC). To assess whether other members of the EGF-family regulate angiogenesis, the expression of 10 EGF-like growth factors in primary ECs and SMCs was analyzed. In addition to HB-EGF, neuregulin-1 (NRG-1) was expressed in ECs in vitro and in vivo. Endothelial NRG-1 was constitutively processed to soluble extracellular and intracellular signaling fragments, and its expression was induced by hypoxia. NRG-1 was angiogenic in vivo in mouse corneal pocket and chicken chorioallantoic membrane (CAM) assays. However, consistent with the lack of NRG-1 receptors in several primary EC lines, NRG-1 did not directly stimulate cellular responses in cultured ECs. In contrast, NRG-1 promoted EC responses in vitro and angiogenesis in CAM in vivo by mechanisms dependent on VEGF-A and VEGFR-2. These results indicate that NRG-1 is expressed by ECs and regulates angiogenesis by mechanisms involving paracrine up-regulation of VEGF-A.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiogenic Proteins / metabolism*
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Angiogenic Proteins / pharmacology
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Cell Hypoxia
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Cell Movement
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Endothelium, Vascular / chemistry
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / metabolism*
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Epidermal Growth Factor / metabolism
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Heparin-binding EGF-like Growth Factor
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Humans
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Intercellular Signaling Peptides and Proteins
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Myocytes, Smooth Muscle / drug effects
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Myocytes, Smooth Muscle / metabolism
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Neovascularization, Physiologic*
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Neuregulin-1 / genetics
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Neuregulin-1 / metabolism*
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Neuregulin-1 / pharmacology
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Paracrine Communication
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Receptor Protein-Tyrosine Kinases / analysis
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Receptor Protein-Tyrosine Kinases / metabolism
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Recombinant Proteins / genetics
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Recombinant Proteins / pharmacology
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Signal Transduction
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Umbilical Cord / cytology
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Up-Regulation
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Vascular Endothelial Growth Factor A / metabolism*
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Vascular Endothelial Growth Factor Receptor-2 / metabolism
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Vascular Endothelial Growth Factors / metabolism
Substances
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Angiogenic Proteins
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HBEGF protein, human
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Hbegf protein, mouse
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Heparin-binding EGF-like Growth Factor
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Intercellular Signaling Peptides and Proteins
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Neuregulin-1
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Recombinant Proteins
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Epidermal Growth Factor
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Receptor Protein-Tyrosine Kinases
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Vascular Endothelial Growth Factor Receptor-2