Hyperglycemia alters the responsiveness of smooth muscle cells to insulin-like growth factor-I
Hyperglycemia alters the responsiveness of smooth muscle cells to insulin-like growth factor-I
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DOI：
10.1210/en.2006-1440
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发表时间：
2007-05-01
期刊：
影响因子：
4.8
通讯作者：
Clemmons, David R.
中科院分区：
文献类型：
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作者：
Maile, Laura A.;Capps, Byron E.;Clemmons, David R.
IGF-I刺激平滑肌细胞(SMC)的迁移和增殖需要αVβ3配体的占据。我们推测，葡萄糖浓度变化引起的细胞外基质蛋白水平的变化可能调节SMC对IGF-I的反应能力。IGF-I可刺激25 mM葡萄糖培养的SMC迁移和增殖，但对5 mM葡萄糖培养的SMC无刺激作用。在25 mM葡萄糖中培养的SMC，IGF-I刺激Shc磷酸化增加，MAPK通路激活，而在5 mM葡萄糖中，IGF-I对Shc磷酸化无影响，MAPK对IGF-I的反应显著降低。在25 mM葡萄糖中生长的细胞，与在5 mM葡萄糖中生长的细胞相比，αVβ3配体，如骨桥蛋白、玻璃体连接蛋白和凝血酶反应蛋白的水平都显著增加。将这些αVβ3配体添加到生长在5 mM葡萄糖中的SMC中，足以使IGF-I刺激的Shc磷酸化和下游信号转导。因为我们以前已经证明，IGF-I刺激的Shc磷酸化和刺激SMC生长需要αVβ3配体占位，我们的数据与25 mM葡萄糖刺激这些细胞外基质蛋白浓度增加的模型一致，从而增加了αVβ3配体占位，从而导致IGF-I刺激Shc磷酸化和促进细胞迁移和增殖。
IGF-I stimulation of smooth muscle cell ( SMC) migration and proliferation requires alpha V beta 3 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 alpha V beta 3 ligands, e. g. osteopontin, vitronectin, and thrombospondin, were all significantly increased, compared with cells grown in 5 mM glucose. The addition of these alpha V beta 3 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 alpha V beta 3 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 alpha V beta 3 ligand occupancy, which leads to increased Shc phosphorylation and enhanced cell migration and proliferation in response to IGF-I.