Mechanical stretch simulates proliferation of venous smooth muscle cells through activation of the insulin-like growth factor-1 receptor

Arterioscler Thromb Vasc Biol. 2007 Aug;27(8):1744-51. doi: 10.1161/ATVBAHA.107.147371. Epub 2007 May 31.


Objective: Activation and proliferation of vascular smooth muscle cells (VSMCs) occur in the venous neointima of vein grafts. VSMCs in a grafted vein are subjected to mechanical stretch; our goal is to understand the essential mechanical stretch-regulated signals that influence VSMCs during neointimal formation in vein grafts.

Methods and results: In cultured vein VSMCs, mechanical stretch induces proliferation and upregulation of both IGF-1 and IGF-1R. Stretch of VSMCs sustained tyrosine phosphorylation of both IGF-1R and its substrate, IRS-1; these responses were related to mechanical stretch-induced activation of Src and autocrine IGF-1 production. Mechanical stretch-activated IGF-1R is functional because there is a prolonged activation of IRS-1-associated phosphatidylinositol-3 kinase (PI3K). When we knocked out IGF-1R, the mechanical stretch-induced increase in VSMC proliferation was blocked. To link mechanical stretch-activated IGF-1R cell signaling to venous VSMC proliferation in vivo, we also studied a vein graft model. Tamoxifen-inducible null deletion of IGF-1R in mice reduced the formation of neointima in the vein graft.

Conclusions: Our results demonstrate for the first time that mechanical stretch activates IGF-1/IGF-1R signals in venous VSMCs, and we have uncovered a signaling pathway that leads to neointima formation in vivo.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Base Sequence
  • Blotting, Western
  • Cell Proliferation*
  • Cells, Cultured
  • Enzyme Activation
  • Immunohistochemistry
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Models, Animal
  • Molecular Sequence Data
  • Muscle, Smooth, Vascular / cytology*
  • Phosphorylation
  • Polymerase Chain Reaction
  • Probability
  • Receptor, IGF Type 1 / metabolism*
  • Sensitivity and Specificity
  • Signal Transduction
  • Stress, Mechanical
  • Tunica Intima / physiology
  • Veins / cytology
  • Veins / physiology


  • Receptor, IGF Type 1