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First published online March 21, 2007
doi: 10.1242/10.1242/jcs.03419

Journal of Cell Science 120, 1256-1266 (2007)
Published by The Company of Biologists 2007
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Research Article

Signaling by ALK5 mediates TGF-beta-induced ET-1 expression in endothelial cells: a role for migration and proliferation

Cristina Castañares1, Mariano Redondo-Horcajo1, Noemi Magán-Marchal1, Peter ten Dijke2, Santiago Lamas1,* and Fernando Rodríguez-Pascual1,*

1 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
2 Department of Molecular Cell Biology, Leiden University Medical Center, Postbus 9600, 2300 RC Leiden, The Netherlands

* Authors for correspondence (e-mail: slamas{at}cib.csic.es; frodriguez{at}cib.csic.es)

Accepted 29 January 2007

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.

Key words: Vascular endothelial cells, Cell migration and proliferation, Angiogenesis, Endothelin-1, Transforming growth factor-beta, ALK5






© The Company of Biologists Ltd 2007