Activin A induces a non-fibrotic phenotype in smooth muscle cells in contrast to TGF-beta

Aims: Activin A and transforming growth factor-beta (TGF-beta) belong to the same family of growth and differentiation factors that modulate vascular lesion formation in distinct ways, which we wish to understand mechanistically. Methods and results: We investigated the expression of cell-surface receptors and activation of Smads in human vascular smooth muscle cells (SMCs) and demonstrated that activin receptor-like kinase-1 (ALK-1), ALK-4, ALK-5 and endoglin are expressed in human SMCs. As expected, TGF-beta 1 activates Smad1 and Smad2 in these cells. Interestingly, activin A also induces phosphorylation of both Smads, which has not been reported for Smad1 before. Transcriptome analyses of activin A and TGF-beta 1 treated SMCs with subsequent Gene-Set Enrichment Analyses revealed that many downstream gene networks are induced by both factors. However, the effect of activin A on expression kinetics of individual genes is less pronounced than for TGF-beta 1, which is explained by a more rapid dephosphorylation of Smads and p38-MAPK in response to activin A. Substantial differences in expression of fibronectin, alpha-v integrin and total extracellular collagen synthesis were observed. Conclusions: Genome-wide mRNA expression analyses clarify the distinct modulation of vascular lesion formation by activin A and TGF-beta 1, most significantly because activin A is non-fibrotic. (C) 2010 Elsevier Inc. All rights reserved