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


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.
Cheng
Jizhong
J
Baylor College of Medicine, Division of Nephrology, Houston, TX 77030, USA.
Du
Jie
J
D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D004789:Enzyme Activation; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D011336:Probability; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D013314:Stress, Mechanical; D017539:Tunica Intima / Q000502:physiology; D014680:Veins / Q000166:cytology / Q000502:physiology
D017526:Receptor, IGF Type 1