Mechanical Stretch Simulates Proliferation of Venous Smooth Muscle Cells Through Activation of the Insulin-Like Growth Factor-1 Receptor

• DOI: 10.1161/atvbaha.107.147371
• Publication Date: 2007-06-01T01:04:47Z
• Authors: Jizhong Cheng; Jie Du
• Keywords: Male; 0301 basic medicine; Base Sequence; Blotting, Western; Molecular Sequence Data; Mice, Transgenic; Immunohistochemistry; Polymerase Chain Reaction; Sensitivity and Specificity; Muscle, Smooth, Vascular; Receptor, IGF Type 1; Enzyme Activation; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Models, Animal; Animals; Phosphorylation; Cells, Cultured; Cell Proliferation; Probability; Signal Transduction

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.