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Basic fibroblast growth factor antagonizes transforming growth factor-beta1-induced smooth muscle gene expression

Keiko Kawai-Kowase1, Hiroko Sato, Yuko Oyama

  • 1Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, 3-Maebashi, Gunma, Japan.

Arteriosclerosis, Thrombosis, and Vascular Biology
|June 26, 2004
PubMed
Abstract

Insights

Basic fibroblast growth factor (bFGF) antagonizes transforming growth factor-beta1 (TGFbeta1) signaling in smooth muscle cells. bFGF suppresses TGFbeta1-induced gene expression by inhibiting serum response factor (SRF) activity, impacting smooth muscle cell plasticity.

Area of Science:

  • Vascular Biology
  • Cell Signaling
  • Molecular Mechanisms

Background:

  • Transforming growth factor-beta1 (TGFbeta1) and fibroblast growth factor (FGF) families are crucial in vascular development and disease.
  • The intracellular signaling interactions between TGFbeta1 and FGF, particularly basic FGF (bFGF), in smooth muscle cells (SMCs) are not fully understood.

Purpose of the Study:

  • To investigate the molecular mechanisms by which TGFbeta1 and bFGF influence SMC gene expression.
  • To elucidate the interplay between TGFbeta1 and bFGF signaling pathways in regulating SMC phenotype.

Main Methods:

  • Examined TGFbeta1 induction of SMC-specific genes (SM22alpha, smooth muscle alpha-actin) in 10T1/2 cells.
  • Utilized c-Src-tyrosine kinase inhibitors, cycloheximide, and promoter analysis (deletion, site-directed mutation) focusing on the SRF-binding CArG box.
  • Assessed the impact of bFGF on TGFbeta1-induced gene expression and promoter activity using transient transfection assays and MEK1 inhibitor (PD98059).

Main Results:

  • TGFbeta1 significantly increased SM22alpha and smooth muscle alpha-actin mRNA levels, an effect inhibited by c-Src inhibitors and cycloheximide.
  • TGFbeta1 activated the SM22alpha promoter via the SRF-binding CArG box and increased SRF gene transcription and expression.
  • bFGF attenuated TGFbeta1-induced SMC marker gene expression by suppressing TGFbeta1's effect on the SM22alpha promoter activity, independent of SRF expression levels, an effect abrogated by PD98059.

Conclusions:

  • bFGF-induced MEK/extracellular signal-regulated kinase (ERK) signaling antagonizes TGFbeta1-mediated SMC gene expression by inhibiting SRF function.
  • The opposing actions of bFGF and TGFbeta1 on SMC gene expression are critical regulators of SMC phenotypic plasticity.

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