Sonic hedgehog signaling induces vascular smooth muscle cell proliferation via induction of the G1 cyclin-retinoblastoma axis

Fenghe Li, Molly Duman-Scheel, Dong Yang, Wei Du, Jian Zhang, Chenchao Zhao, Lingfeng Qin, Shijie Xin

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

Objective: Proliferation of vascular smooth muscle cells (VSMCs) is a crucial event in the pathogenesis of intimal hyperplasia, the main cause of restenosis following vascular reconstruction. Here, the impact of sonic hedgehog (Shh)/Gli family zinc finger 2 (Gli2) signaling on VSMC proliferation was assessed. Methods and Results: Increased Shh signaling was detected in VSMCs in the neointima of vein grafts obtained from mice undergoing restenosis. Comparable results were found in primary cultured human VSMCs (hVSMCs) obtained from patients undergoing coronary bypass surgery, which were used to further assess the impacts of Shh signaling on VSMC proliferation. Inhibition of Shh signaling in hVSMCs through treatment with cyclopamine or knockdown of Gli2 results in G1 arrest and reduced cyclin D1, cyclin E, and phosphorylated retinoblastoma (pRB) levels. In contrast, activation of Shh/Gli2 signaling in hVSMCs results in increased levels of G1 cyclins and promotes G1-S transition. Stimulation of hVSMC proliferation by Shh is abolished by cyclin D1 knockdown. Conclusion: Combined, these results demonstrate that Shh/Gli2 signaling stimulates VSMC proliferation via regulation of the G1 cyclin-retinoblastoma axis and suggest that antagonists that target the Shh pathway may be therapeutically beneficial in the prevention of intimal hyperplasia.

Original languageEnglish (US)
Pages (from-to)1787-1794
Number of pages8
JournalArteriosclerosis, thrombosis, and vascular biology
Volume30
Issue number9
DOIs
StatePublished - Sep 2010

Keywords

  • cell cycle
  • hedgehog signaling
  • intimal hyperplasia
  • proliferation
  • vascular smooth muscle cell

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Medicine(all)

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