Cthrc1 is a novel inhibitor of transforming growth factor-beta signaling and neointimal lesion formation

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Renée J LeClair1, Tahir Durmus, Qiaozeng Wang

  • 1Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME 04074, USA.

Circulation Research
|February 27, 2007
PubMed

Insights

Collagen triple helix repeat containing-1 (Cthrc1) reduces arterial collagen deposition and neointimal formation by inhibiting transforming growth factor-beta signaling in smooth muscle cells. This gene impacts cell migration and collagen production in vascular injury responses.

Area of Science:

  • Vascular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Collagen triple helix repeat containing-1 (Cthrc1) is a novel gene identified in arterial adventitia and neointima following injury.
  • Cthrc1 influences cell migration and collagen deposition, suggesting a role in vascular remodeling.

Purpose of the Study:

  • To investigate the in vivo function of Cthrc1 in arterial injury response.
  • To elucidate the molecular mechanisms by which Cthrc1 affects vascular smooth muscle cells and extracellular matrix production.

Main Methods:

  • Generation of transgenic mouse lines overexpressing Cthrc1.
  • Carotid artery ligation model to induce arterial injury.
  • Alcian blue staining and collagen type II expression analysis for cartilaginous metaplasia.
  • Western blot analysis for phospho-Smad2/3 and procollagen levels.
  • Transforming growth factor-beta (TGF-β) reporter assays in smooth muscle and endothelial cells.

Main Results:

  • Constitutive Cthrc1 overexpression in mice led to brittle bones due to reduced collagenous bone matrix.
  • Hemizygous Cthrc1 transgenic mice exhibited significantly reduced neointimal lesion formation and adventitial collagen deposition after carotid artery ligation.
  • A high percentage (75%) of Cthrc1 transgenic mice showed cartilaginous metaplasia in medial smooth muscle cells.
  • Cthrc1 overexpression reduced TGF-β signaling (phospho-Smad2/3) in smooth muscle cells of transgenic arteries and in cultured cells, decreasing procollagen levels.
  • Cthrc1 specifically inhibited TGF-β-sensitive reporter constructs in smooth muscle cells, but not in endothelial cells.

Conclusions:

  • Cthrc1 acts as a cell-type-specific inhibitor of TGF-β signaling, primarily in smooth muscle cells.
  • Cthrc1 negatively regulates collagen type I and III deposition, impacting neointimal hyperplasia and vascular remodeling.
  • Cthrc1 plays a significant role in preventing smooth muscle cell dedifferentiation and contributes to maintaining vascular integrity post-injury.

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