title: Intra- and extracellular signaling by endothelial neuregulin-1.
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.
authors.affiliation: Department of Medical Biochemistry and Molecular Biology, and Medicity Research Laboratories, University of Turku, Turku, Finland.
authors.forename: Erika
authors.initials: E
authors.lastname: Iivanainen
authors.forename: Ilkka
authors.initials: I
authors.lastname: Paatero
authors.forename: Satu-Maria
authors.initials: SM
authors.lastname: Heikkinen
authors.forename: Teemu T
authors.initials: TT
authors.lastname: Junttila
authors.forename: Renhai
authors.initials: R
authors.lastname: Cao
authors.forename: Peter
authors.initials: P
authors.lastname: Klint
authors.forename: Panu M
authors.initials: PM
authors.lastname: Jaakkola
authors.forename: Yihai
authors.initials: Y
authors.lastname: Cao
authors.forename: Klaus
authors.initials: K
authors.lastname: Elenius
mesh_terms: D042501:Angiogenic Proteins / Q000378:metabolism* / Q000494:pharmacology; D015687:Cell Hypoxia; D002465:Cell Movement; D004730:Endothelium, Vascular / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D018919:Neovascularization, Physiologic; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D019899:Paracrine Communication; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D015398:Signal Transduction; D014470:Umbilical Cord / Q000166:cytology; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D042442:Vascular Endothelial Growth Factors / Q000378:metabolism
chemical_list: D042501:Angiogenic Proteins; C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D020890:Neuregulin-1; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D004815:Epidermal Growth Factor; D020794:Receptor Protein-Tyrosine Kinases; D040301:Vascular Endothelial Growth Factor Receptor-2