Signaling by ALK5 mediates TGF-beta-induced ET-1 expression in endothelial cells: a role for migration and proliferation.
Endothelin-1 (ET-1) is a potent endothelial-derived 21-amino-acid vasoconstrictor peptide and its expression is potently regulated by the cytokine transforming growth factor-beta (TGF-beta). Most cell types contain a TGF-beta type I receptor form known as activin receptor-like kinase 5 (ALK5). However, endothelial cells coexpress an additional type I receptor named ALK1. These forms do not constitute redundant receptors with the same function, but they activate different Smad-mediated expression programmes leading to specific endothelial phenotypes. The aim of our study was to characterize the TGF-beta-induced pathway leading to ET-1 expression in endothelial cells and the contribution of the TGF-beta-mediated enhancement of ET-1 to the regulation of the endothelial cell migration and proliferation capacity. Our experiments indicate that TGF-beta induces ET-1 expression preferentially through the ALK5/Smad3 pathway. Specific ALK5 inhibition totally blocked the anti-angiogenic effect of TGF-beta. Antagonism of ET receptors partially reverted the effect of TGF-beta, indicating that a significant portion of the anti-migratory and anti-proliferative actions of this cytokine is mediated by ET-1 acting in an autocrine manner on endothelial cells.
Castañares
Cristina
C
Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (C.S.I.C.), Instituto Reina Sofía de Investigaciones Nefrológicas, Ramiro de Maeztu 9, 28040 Madrid, Spain.
Redondo-Horcajo
Mariano
M
Magán-Marchal
Noemi
N
ten Dijke
Peter
P
Lamas
Santiago
S
Rodríguez-Pascual
Fernando
F
D030201:Activin Receptors, Type I / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology; D015153:Blotting, Western; D002417:Cattle; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology; D016650:Fluorescein-5-isothiocyanate; D005456:Fluorescent Dyes; D005786:Gene Expression Regulation / Q000187:drug effects*; D017930:Genes, Reporter; D007700:Kinetics; D008156:Luciferases / Q000032:analysis / Q000378:metabolism; D008856:Microscopy, Fluorescence; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D019332:Endothelin-1; D005456:Fluorescent Dyes; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016212:Transforming Growth Factor beta; D008156:Luciferases; D030201:Activin Receptors, Type I; D016650:Fluorescein-5-isothiocyanate