Published online before print February 3, 2005, doi: 10.1161/01.RES.0000157671.47477.71
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Submitted on August 9, 2004
Revised on January 18, 2005
Accepted on January 20, 2005
Insulin-Like Growth Factor-I Regulates Proliferation and Osteoblastic Differentiation of Calcifying Vascular Cells via Extracellular Signal-Regulated Protein Kinase And Phosphatidylinositol 3-Kinase Pathways
K. Radcliff ;
From the Geffen School of Medicine at UCLA (T.B.T., J.L., Z.Z., M.A., L.L.D., Y.T.), Los Angeles, Calif; and Duke University School of Medicine (K.R.), Durham, NC.
* To whom correspondence should be addressed. E-mail: ytintut{at}mednet.ucla.edu.
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-
, 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.
Key words: vascular • calcification • IGF-I • atherosclerosis
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