title: Vasoactive peptides modulate vascular endothelial cell growth factor production and endothelial cell proliferation and invasion.
abstract: The proliferation of vascular endothelial cells (EC) is an important event in angiogenesis. The synthesis of the EC growth factor, vascular endothelial cell growth factor (VEGF), is stimulated by a variety of activators; but the effects of important vasoactive peptides are not well understood, and there are no known natural inhibitors of VEGF production. We found that the vasoactive peptides endothelin (ET)-1 and ET-3 stimulated the synthesis of VEGF protein 3-4-fold in cultured human vascular smooth muscle cells, comparable in magnitude to hypoxia. ET-1 and ET-3 acted through the ETA and ETB receptors, respectively, and signaling through protein kinase C was important. Atrial natriuretic peptide (ANP), C-type natriuretic peptide, and C-ANP-(4-23), a ligand for the natriuretic peptide clearance receptor, equipotently inhibited production of VEGF by as much as 88% and inhibited ET- or hypoxia-stimulated VEGF transcription. EC proliferation and invasion of matrix were stimulated by VEGF secreted into the medium by ET-incubated vascular smooth muscle cells. This was inhibited by ANP. Our results identify the natriuretic peptides as the first peptide inhibitors of VEGF synthesis and indicate a novel mechanism by which vasoactive peptides could modulate angiogenesis.
authors.affiliation: Department of Medicine, University of California, Irvine, California 92717, USA.
authors.forename: A
authors.initials: A
authors.lastname: Pedram
authors.forename: M
authors.initials: M
authors.lastname: Razandi
authors.forename: R M
authors.initials: RM
authors.lastname: Hu
authors.forename: E R
authors.initials: ER
authors.lastname: Levin
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism*; D002417:Cattle; D002455:Cell Division; D016228:Endothelial Growth Factors / Q000096:biosynthesis* / Q000235:genetics; D019332:Endothelin-1 / Q000378:metabolism*; D019334:Endothelin-3 / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D008222:Lymphokines / Q000096:biosynthesis* / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D020098:Natriuretic Peptide, C-Type; D018919:Neovascularization, Physiologic; D014176:Protein Biosynthesis; D021382:Protein Sorting Signals / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017466:Receptors, Endothelin / Q000378:metabolism; D014158:Transcription, Genetic; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D016228:Endothelial Growth Factors; D019332:Endothelin-1; D019334:Endothelin-3; D008222:Lymphokines; D021382:Protein Sorting Signals; D011506:Proteins; D012333:RNA, Messenger; D017466:Receptors, Endothelin; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020098:Natriuretic Peptide, C-Type; D009320:Atrial Natriuretic Factor; D019204:GTP-Binding Proteins