Abstract
Vascular calcification develops within atherosclerotic lesions and results from a process similar to osteogenesis. One of the paracrine regulators of bone-derived osteoblasts, insulin-like growth factor-I (IGF-I), is also present in atherosclerotic lesions. To evaluate its possible role in vascular calcification, we assessed its in vitro effects on proliferation and differentiation in calcifying vascular cells (CVCs), a subpopulation of bovine aortic medial cells. Results showed that IGF-I inhibited spontaneous CVC differentiation and mineralization as evidenced by decreased alkaline phosphatase (AP) activity and decreased matrix calcium incorporation, respectively. Furthermore, IGF-I inhibited the AP activity induced by bacterial lipopolysaccharide, TNF-alpha, or H2O2. It also induced CVC proliferation based on 3H-thymidine incorporation. Results from Northern analysis and tests using IGF-I analogs suggest that IGF-I effects are mediated through the IGF-I receptor. IGF-I also activated both the extracellular signal-regulated protein kinase (ERK) and phosphatidylinositol 3-kinase (PI3K) pathways. Inhibition of either the ERK or PI3K pathway reversed IGF-I effects on CVC proliferation and AP activity, suggesting a common downstream target. Overexpression of ERK activator also mimicked IGF-I inhibition of lipopolysaccharide-induced AP activity. These results suggest that IGF-I promotes proliferation and inhibits osteoblastic differentiation and mineralization of vascular cells via both ERK and PI3K pathways.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Alkaline Phosphatase / analysis
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Animals
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Aorta / cytology*
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Aortic Diseases / physiopathology*
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Becaplermin
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Calcinosis / physiopathology*
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Calcium / metabolism
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Cattle
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Cell Differentiation / drug effects
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Cell Division / drug effects
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Cells, Cultured / drug effects
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Chromones / pharmacology
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DNA-Binding Proteins / physiology
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Extracellular Matrix / metabolism
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Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
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Extracellular Signal-Regulated MAP Kinases / physiology*
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Flavonoids / pharmacology
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Humans
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Insulin-Like Growth Factor I / genetics
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Insulin-Like Growth Factor I / pharmacology*
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Insulin-Like Growth Factor I / physiology
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Lipopolysaccharides / pharmacology
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MAP Kinase Kinase Kinases / genetics
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MAP Kinase Kinase Kinases / physiology
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Morpholines / pharmacology
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Osteoblasts / drug effects*
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Osteoblasts / pathology
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Phosphatidylinositol 3-Kinases / physiology*
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Platelet-Derived Growth Factor / pharmacology
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Protein Serine-Threonine Kinases / physiology
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Proto-Oncogene Proteins / physiology
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Proto-Oncogene Proteins c-akt
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Proto-Oncogene Proteins c-sis
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Receptor, IGF Type 1 / drug effects
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Receptor, IGF Type 1 / physiology
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Recombinant Proteins / pharmacology
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Signal Transduction / drug effects*
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Signal Transduction / physiology
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Transcription Factors / physiology
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Transfection
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Tumor Necrosis Factor-alpha / pharmacology
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Tunica Media / cytology*
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ets-Domain Protein Elk-1
Substances
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Chromones
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DNA-Binding Proteins
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Flavonoids
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Lipopolysaccharides
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Morpholines
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Platelet-Derived Growth Factor
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-sis
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Recombinant Proteins
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Transcription Factors
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Tumor Necrosis Factor-alpha
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ets-Domain Protein Elk-1
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Becaplermin
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Insulin-Like Growth Factor I
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Receptor, IGF Type 1
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases
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MAP Kinase Kinase Kinases
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Alkaline Phosphatase
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
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Calcium