Transforming growth factor-beta induces loss of epithelial character and smooth muscle cell differentiation in epicardial cells.
During embryogenesis, epicardial cells undergo epithelial-mesenchymal transformation (EMT), invade the myocardium, and differentiate into components of the coronary vasculature, including smooth muscle cells. We tested the hypothesis that transforming growth factor-beta (TGFbeta) stimulates EMT and smooth muscle differentiation of epicardial cells. In epicardial explants, TGFbeta1 and TGFbeta2 induce loss of epithelial morphology, cytokeratin, and membrane-associated Zonula Occludens-1 and increase the smooth muscle markers calponin and caldesmon. Inhibition of activin receptor-like kinase (ALK) 5 blocks these effects, whereas constitutively active (ca) ALK5 increases cell invasion by 42%. Overexpression of Smad 3 did not mimic the effects of caALK5. Inhibition of p160 rho kinase or p38 MAP kinase prevented the loss of epithelial morphology in response to TGFbeta, whereas only inhibition of p160 rho kinase blocked TGFbeta-stimulated caldesmon expression. These data demonstrate that TGFbeta stimulates loss of epithelial character and smooth muscle differentiation in epicardial cells by means of a mechanism that requires ALK5 and p160 rho kinase.
Compton
Leigh A
LA
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232-6600, USA.
Potash
Dru A
DA
Mundell
Nathan A
NA
Barnett
Joey V
JV
D030201:Activin Receptors, Type I / Q000502:physiology; D000818:Animals; D002148:Calmodulin-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D002454:Cell Differentiation / Q000502:physiology*; D002642:Chick Embryo; D004848:Epithelium / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D009924:Organ Culture Techniques; D010496:Pericardium / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology; D054460:rho-Associated Kinases
D002148:Calmodulin-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I