Transforming growth factor-β-dependent growth inhibition in primary vascular smooth muscle cells is p38-dependent

Academic Article

Abstract

  • Vascular smooth muscle cells (VSMCs) constitute the major cellular component of the vessel tunica media. VSMC proliferation is a key feature in developing vessels and pathological states such as atherosclerosis and restenosis. Transforming growth factor (TGF)-β is a key regulator of VSMCs, but its effect on VSMC proliferation and apoptosis are controversial. Here, we characterized TGF-β effects on basal-, serum-, and platelet-derived growth factor-BB-induced primary mouse VSMC proliferation. TGF-β led to potent growth inhibition of VSMCs isolated from normal mouse aortae without inducing apoptosis. Growth inhibition by TGF-β was due to G0/G 1 arrest. Next, we explored distinct signaling pathways activated by TGF-β and the effects of pharmacological inhibition of these. TGF-β led to activation of Smad2/3, p38, p42/44, and c-Jun NH2-terminal kinase (JNK) pathways, assessed by phosphorylation, immunofluorescence, and reporter gene analysis. TGF-β-dependent growth inhibition was specifically attenuated by pharmacological blockade of the TGF-β type I receptor (TβRI) kinase or p38 mitogen-activated protein kinase pathways, whereas blockade of p42/44 or JNK kinases did not influence the effect of TGF-β. TβRI kinase inhibition blocked all downstream pathways including Smad and p38 phosphorylation. In contrast, p38 inhibition did not alter Smad function, as assessed by translocation or reporter gene expression, but selectively inhibited p38 activity. These results demonstrate that TGF-β acts as a potent antiproliferative mediator in VSMCs, irrespective of the proliferative stimulus, without inducing apoptotic effects. The antiproliferative effect of TGF-β is due to G0/G1 arrest and mediated primarily by the p38 pathway, suggesting that p38 kinase is central to TGF-β-mediated growth inhibition in primary mouse VSMCs. Copyright © 2005 by The American Society for Pharmacology and Experimental Therapeutics.
  • Authors

    Digital Object Identifier (doi)

    Author List

  • Seay U; Sedding D; Krick S; Hecker M; Seeger W; Eickelberg O
  • Start Page

  • 1005
  • End Page

  • 1012
  • Volume

  • 315
  • Issue

  • 3