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

Bianca C W Groenendijk; Germaine F J D Benus; Anita Klous; Yolanda M Pacheco; Oscar L Volger; Joost O Fledderus; Valerie Ferreira; Marten A Engelse; Hans Pannekoek; Peter ten Dijke; Anton J G Horrevoets; Carlie J M de Vries

doi:10.1016/j.yexcr.2010.10.007

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

Exp Cell Res. 2011 Jan 15;317(2):131-42. doi: 10.1016/j.yexcr.2010.10.007. Epub 2010 Oct 15.

Authors

Bianca C W Groenendijk¹, Germaine F J D Benus, Anita Klous, Yolanda M Pacheco, Oscar L Volger, Joost O Fledderus, Valerie Ferreira, Marten A Engelse, Hans Pannekoek, Peter ten Dijke, Anton J G Horrevoets, Carlie J M de Vries

Affiliation

¹ Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, The Netherlands.

PMID: 20955695
DOI: 10.1016/j.yexcr.2010.10.007

Abstract

Aims: Activin A and transforming growth factor-β1 (TGF-β1) 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-β1 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-β1 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-β1, 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-β1, most significantly because activin A is non-fibrotic.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

Activin Receptors, Type I / metabolism
Activin Receptors, Type II / metabolism*
Activins / genetics
Activins / metabolism
Activins / pharmacology*
Cells, Cultured
Endothelium, Vascular / cytology
Humans
Myocytes, Smooth Muscle / cytology*
Myocytes, Smooth Muscle / drug effects*
Myocytes, Smooth Muscle / metabolism
Phenotype*
Phosphorylation / drug effects
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism
Receptors, Growth Factor / biosynthesis
Receptors, Growth Factor / genetics
Receptors, Growth Factor / metabolism
Recombinant Proteins / metabolism
Recombinant Proteins / pharmacology
Saphenous Vein / cytology
Smad2 Protein / metabolism
Transforming Growth Factor beta / genetics
Transforming Growth Factor beta / metabolism
Transforming Growth Factor beta / pharmacology*
Transforming Growth Factor beta1 / genetics
Transforming Growth Factor beta1 / metabolism
p38 Mitogen-Activated Protein Kinases / genetics
p38 Mitogen-Activated Protein Kinases / metabolism

Substances

Receptors, Growth Factor
Recombinant Proteins
SMAD2 protein, human
Smad2 Protein
Transforming Growth Factor beta
Transforming Growth Factor beta1
activin A
Activins
Protein Serine-Threonine Kinases
p38 Mitogen-Activated Protein Kinases
ACVR1B protein, human
ACVRL1 protein, human
Activin Receptors, Type I
Activin Receptors, Type II