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First published online March 21, 2007
doi: 10.1242/10.1242/jcs.03419
Research Article |
-induced ET-1 expression in endothelial cells: a role for migration and proliferation
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-
(TGF-). Most cell types contain a TGF- 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--induced pathway leading to ET-1 expression in endothelial cells and the contribution of the TGF--mediated enhancement of ET-1 to the regulation of the endothelial cell migration and proliferation capacity. Our experiments indicate that TGF- induces ET-1 expression preferentially through the ALK5/Smad3 pathway. Specific ALK5 inhibition totally blocked the anti-angiogenic effect of TGF-. Antagonism of ET receptors partially reverted the effect of TGF-, 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-, ALK5
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