Hyperglycemia Alters the Responsiveness of Smooth Muscle Cells to Insulin-Like Growth Factor-I

• Published in: Endocrinology (Philadelphia) 2007-05, Vol.148 (5), p.2435-2443
• Main Authors: Maile, Laura A, Capps, Byron E, Ling, Yan, Xi, Gang, Clemmons, David R
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Animals; Aorta - cytology; Cell activation; Cell Division - drug effects; Cell Division - physiology; Cell migration; Cell Movement - drug effects; Cell Movement - physiology; Cell proliferation; CHO Cells; Cricetinae; Cricetulus; Extracellular matrix; Extracellular Matrix - metabolism; Extracellular Signal-Regulated MAP Kinases - metabolism; Glucose; Glucose - pharmacology; Growth factors; Humans; Hyperglycemia; Hyperglycemia - metabolism; Insulin-like growth factor I; Insulin-Like Growth Factor I - metabolism; Insulin-Like Growth Factor I - pharmacology; Insulin-like growth factors; Integrin alphaVbeta3 - metabolism; Ligands; MAP kinase; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Osteopontin; Osteopontin - metabolism; Phosphorylation; Phosphorylation - drug effects; Proteins; Shc Signaling Adaptor Proteins; Signal Transduction - drug effects; Signal Transduction - physiology; Smooth muscle; Src Homology 2 Domain-Containing, Transforming Protein 1; Stimulation; Swine; Thrombospondin; Thrombospondins - metabolism; Vitronectin; Vitronectin - metabolism
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2006-1440

IGF-I stimulation of smooth muscle cell (SMC) migration and proliferation requires αVβ3 ligand occupancy. We hypothesized that changes in the levels of extracellular matrix proteins induced by alterations in glucose concentrations may regulate the ability of SMCs to respond to IGF-I. IGF-I stimulated migration and proliferation of SMCs that had been maintained in 25 mm glucose containing media, but it had no stimulatory effect when tested using SMCs that had been grown in 5 mm glucose. IGF-I stimulated an increase in Shc phosphorylation and enhanced activation of the MAPK pathway in SMCs grown in 25 mm glucose, whereas in cells maintained in 5 mm glucose, IGF-I had no effect on Shc phosphorylation, and the MAPK response to IGF-I was markedly reduced. In cells grown in 25 mm glucose, the levels of αVβ3 ligands, e.g. osteopontin, vitronectin, and thrombospondin, were all significantly increased, compared with cells grown in 5 mm glucose. The addition of these αVβ3 ligands to SMCs grown in 5 mm glucose was sufficient to permit IGF-I-stimulated Shc phosphorylation and downstream signaling. Because we have shown previously that αVβ3 ligand occupancy is required for IGF-I-stimulated Shc phosphorylation and stimulation of SMC growth, our data are consistent with a model in which 25 mm glucose stimulates increases in the concentrations of these extracellular matrix proteins, thus enhancing αVβ3 ligand occupancy, which leads to increased Shc phosphorylation and enhanced cell migration and proliferation in response to IGF-I.