• ALK;
  • angiogenesis;
  • signal transduction;
  • Smad;
  • TGF-β

The generation of mice lacking specific components of the transforming growth factor-β (TGF-β) signal tranduction pathway shows that TGF-β is a key player in the development and physiology of the cardiovascular system. Both pro- and anti-angiogenic properties have been ascribed to TGF-β, for which the molecular mechanisms are unclear. Here we report that TGF-β can activate two distinct type I receptor/Smad signalling pathways with opposite effects. TGF-β induces phosphorylation of Smad1/5 and Smad2 in endothelial cells and these effects can be blocked upon selective inhibition of ALK1 or ALK5 expression, respectively. Whereas the TGF-β/ALK5 pathway leads to inhibition of cell migration and proliferation, the TGF-β/ALK1 pathway induces endothelial cell migration and proliferation. We identified genes that are induced specifically by TGF-β-mediated ALK1 or ALK5 activation. Id1 was found to mediate the TGF-β/ALK1-induced (and Smad-dependent) migration, while induction of plasminogen activator inhibitor-1 by activated ALK5 may contribute to the TGF-β-induced maturation of blood vessels. Our results suggest that TGF-β regulates the activation state of the endothelium via a fine balance between ALK5 and ALK1 signalling.