Abstract
Mechanical forces are well known to modulate smooth muscle cell growth and synthetic phenotype. The signals controlling this process are complex and potentially involve changes in the expression of peptide growth factor genes such as those of the insulin‐like growth factor (IGF) system. This study was designed to investigate the mechanical regulation of IGF‐I and the binding proteins for IGF (IGFBPs) in smooth muscle cells cultured on a deformable surface and subjected to cyclic stretch. Using the RNase protection assay, we found that the application of a cyclic biaxial strain to cells induced a 2.5‐ to 4‐fold increase in IGF‐I mRNA levels after 8 h and an even greater increase after 16–24 h of stretch. This change was not affected by variations in the magnitude of the applied strain but was attenuated (∼40%) when cells were treated with antagonists for angiotensin II receptors. Furthermore, the transcript levels of the three major IGF binding proteins produced in smooth muscle cells, e.g., IGFBP‐2, IGFBP‐4, and IGFBP‐5, varied between stretched and control cells. Both IGFBP‐2 and IGFBP‐4 mRNA levels were consistently reduced in stretched cells but remained comparable to those of the control cells when the angiotensin II transducing pathway was blocked by inhibitors prior to the application of mechanical strain. Conversely, the gene expression of IGFBP‐5 was upregulated in stretched cells, and neutralizing antibodies to IGF‐I blocked this activation. Similarly, pharmacologic inhibition of the phosphatidylinositol 3‐kinase, an important component of the IGF receptor transduction pathway, inhibited IGFBP‐5 gene expression in stretched cells. These results suggest that the downstream effects of mechanical strain on IGF‐I and IGFBP transcript levels are mediated, to greater or lesser extent, either through an angiotensin II tranducing pathway or via a feedback loop involving the autocrine secretion of IGF‐I itself. J. Cell. Biochem. 84: 264–277, 2002. © 2001 Wiley‐Liss, Inc.