Intra- and extracellular signaling by endothelial neuregulin-1.
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.
Iivanainen
Erika
E
Department of Medical Biochemistry and Molecular Biology, and Medicity Research Laboratories, University of Turku, Turku, Finland.
Paatero
Ilkka
I
Heikkinen
Satu-Maria
SM
Junttila
Teemu T
TT
Cao
Renhai
R
Klint
Peter
P
Jaakkola
Panu M
PM
Cao
Yihai
Y
Elenius
Klaus
K
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
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