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      Different Growth Properties of Neointimal and Medial Smooth Muscle Cells in Response to Growth Factors


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          Different smooth muscle cell phenotypes coexist in arteries. The majority of cells cultured from a normal rat aortic media have a spindle-shaped phenotype while cells isolated from an intimal thickening 15 days after endothelial injury show a distinct epithelioid phenotype. These two phenotypes express their own specific set of genes and differ in their proliferation and migration characteristics. We studied growth factor-induced DNA synthesis in both phenotypes and investigated the potential mechanisms behind the differences in growth characteristics. Insulin-like growth factor-I (IGF-I), platelet-derived growth factor (PDGF-BB), and basic fibroblast growth factor (FGF) increased thymidine incorporation in both phenotypes, but the increase was markedly stronger in neointimal cells than in medial cells. Northern blot analysis 30 min after growth factor stimulation showed that c- fos and c- jun mRNAs were induced more strongly in neointimal than in medial cells. IGF-I receptor and PDGF-Rβ levels were higher in neointimal cells than in medial cells, but the FGF receptor level was not different between the cell types. In summary, our results indicate that neointimal cells are more sensitive to growth factors than medial cells, likely due to a higher expression of IGF-I receptor and PDGF-Rβ. Our results provide insight into the mechanism by which epithelioid cells play a primary role in vascular neointima formation.

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          Most cited references 5

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          Insulin-like growth factors and their binding proteins: biological actions

           J Jones (1995)
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            Recombinant fibroblast growth factor-1 promotes intimal hyperplasia and angiogenesis in arteries in vivo.

            The prototype members of the heparin-binding fibroblast growth factor (FGF) family, acidic FGF (FGF-1) and basic FGF (FGF-2), are among the growth factors that act directly on vascular cells to induce endothelial cell growth and angiogenesis. In vivo, the role of the FGF prototypes in vascular pathology has been difficult to determine. We report here the introduction, by direct gene transfer into porcine arteries, of a eukaryotic expression vector encoding a secreted form of FGF-1. This somatic transgenic model defines gene function in the arterial wall in vivo. FGF-1 expression induced intimal thickening in porcine arteries 21 days after gene transfer, in contrast to control arteries transduced with an Escherichia coli beta-galactosidase gene. Where there was substantial intimal hyperplasia, neocapillary formation was detected in the expanded intima. These findings suggest that FGF-1 induces intimal hyperplasia in the arterial wall in vivo and, through its ability to stimulate angiogenesis in the neointima, FGF-1 could stimulate neovascularization of atherosclerotic plaques. Potentially, gene transfer of FGF-1 could also be used as a genetic intervention to improve blood flow to ischaemic tissues in selected clinical settings.
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              Differential expression and biological effects of insulin-like growth factor-binding protein-4 and -5 in vascular smooth muscle cells.

               C Duan,  D Clemmons (1998)
              Insulin-like growth factor-I (IGF-I) plays an important role in regulating vascular smooth muscle cell (VSMC) proliferation, migration, and apoptosis. The bioactivity of IGF-I is modulated by a group of high affinity, specific binding proteins (IGF-binding proteins; IGFBPs) that are present in the interstitial fluid. Previously, we have reported that porcine VSMCs synthesize and secrete IGF-I and several forms of IGFBPs, including IGFBP-2, IGFBP-4, and IGFBP-5. In this study, we examined the role of autocrine/paracrine secreted IGF-I in controlling the expression of IGFBP-4 and IGFBP-5 as well as the effects of these IGFBPs in modulating the cellular replication response to IGF-I. The concentrations of IGFBP-4 in the conditioned medium increased significantly from <50 ng/ml to 742 +/- 105 ng/ml. This increase was associated with a decrease in the activity of an IGF-I-regulated IGFBP-4 protease. In contrast, the synthesis of IGFBP-5 was inversely correlated with culture density, and its concentration decreased from 792 +/- 91 to 44 +/- 14 ng/ml. IGFBP-5 mRNA in sparse cultures was 3-fold higher compared with those in confluent cultures. This culture density-dependent change in IGFBP-5 mRNA correlated closely with endogenous IGF-I levels. Since treatment of VSMC with exogenous IGF-I increased IGFBP-5 mRNA levels, we neutralized the effect of endogenously secreted IGF-I with an anti-IGF-I antibody to determine if it would alter IGFBP-5 mRNA abundance. This resulted in a 4.4-fold decrease in IGFBP-5 mRNA levels. When added together with IGF-I, exogenous IGFBP-4 inhibited IGF-I-induced DNA synthesis in a concentration-dependent manner. IGFBP-5, on the other hand, potentiated the effect of IGF-I. Therefore, IGFBP-4 and IGFBP-5 appear to be differentially regulated by autocrine/paracrine IGF-I through distinct mechanisms. These two proteins, in turn, play opposing roles in modulating IGF-I action in stimulating VSMC proliferation.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                April 2003
                19 June 2003
                : 40
                : 2
                : 97-104
                aDivision of Cardiology, Fondation pour Recherches Médicales, and bDepartment of Pathology, Centre Médical Universitaire, Geneva, Switzerland
                70706 J Vasc Res 2003;40:97–104
                © 2003 S. Karger AG, Basel

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                Page count
                Figures: 5, Tables: 1, References: 35, Pages: 8
                Research Paper


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