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Forkhead transcription factors inhibit vascular smooth muscle cell proliferation and neointimal hyperplasia

Md Ruhul Abid1, Kiichiro Yano, Shaodong Guo

  • 1Center for Vascular Biology Research, Department of Medicine, Division of Molecular and Vascular Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.

The Journal of Biological Chemistry
|June 18, 2005
PubMed

Insights

Forkhead box O (FoxO) proteins inhibit vascular smooth muscle cell (VSMC) proliferation. Activating FoxO signaling may offer a therapeutic strategy for preventing VSMC-driven vascular diseases like atherosclerosis.

Area of Science:

  • Vascular biology
  • Molecular signaling
  • Cellular proliferation

Background:

  • Vascular smooth muscle cell (VSMC) proliferation and migration are key drivers of atherosclerosis, restenosis, and transplant vasculopathy.
  • Forkhead transcription factors (FoxO) are known to inhibit cell growth and cell cycle progression.
  • The role of FoxO proteins in VSMC biology was investigated.

Purpose of the Study:

  • To determine if FoxO proteins influence VSMC proliferation and migration.
  • To elucidate the signaling pathways regulating FoxO activity in VSMCs.
  • To assess the therapeutic potential of FoxO activation in preventing VSMC-mediated vascular diseases.

Main Methods:

  • Human coronary artery smooth muscle cells (CASMCs) were treated with growth factors (PDGF-BB, TNF-α, IGF-1) to induce FoxO phosphorylation.
  • FoxO localization, target gene expression (p27kip1), and cell cycle progression were analyzed.
  • A constitutively active FoxO mutant (TM-FKHRL1) and small interfering RNA (siRNA) against p27kip1 were used.
  • Adenovirus-mediated FKHRL1 gene transfer was performed in a rat balloon carotid arterial injury model.

Main Results:

  • Growth factors stimulated FoxO phosphorylation and nuclear exclusion in CASMCs.
  • PDGF-BB downregulated the FoxO target gene p27kip1, promoting cell cycle progression.
  • Overexpression of TM-FKHRL1 inhibited VSMC proliferation and increased p27kip1 expression.
  • FKHRL1 gene transfer reduced neointimal hyperplasia in vivo, with increased p27kip1 expression.

Conclusions:

  • FoxO activity inhibits VSMC proliferation and activation.
  • The FoxO signaling pathway is a potential therapeutic target for vasculopathic diseases.

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