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INHIBITION OF SMOOTH MUSCLE CELL MIGRATION AND PROLIFERATION WITH SOLUBLE N-CADHERIN

C. A. Lyon, G. B. Sala-Newby, S. J. George. Bristol Heart Institute, University of Bristol. Brsitol, UK

Vascular smooth muscle cell (VSMC) proliferation and migration are key contributors to atherosclerosis and restenosis. The cell-cell adhesion molecule N-cadherin is the predominant cadherin expressed by VSMCs and affects several cell signalling pathways including β-catenin and FGF-R. N-cadherin modulates VSMC proliferation and migration. In this study we have examined whether a soluble form of N-cadherin (SNC) acts as a mimetic, inhibiting VSMC proliferation and migration. SNC (200 pM) significantly reduced human VSMC proliferation (4.3%±1.0 versus 14.2%±2.5, n = 3, p<0.05) and migration (distance migrated: 276±38 μm versus 389±9 μm, n = 5, p<0.05), as assessed by BrdU incorporation and wounding assay, respectively. Interestingly, SNC did not affect full-length N-cadherin stability. Using TOPgal VSMCs, expressing the β-galactosidase gene controlled by the β-catenin promoter we found that SNC did not affect β-catenin signalling during proliferation. There was no difference in β-galactosidase activity (1015±192 vs 941±147 luminescence arbitrary units, n = 3) and no difference in the percentage of BrdU and β-catenin signalling positive cells detected by dual immunocytochemistry (58.7±7% vs 58.4±3%, n = 3). In contrast, SNC significantly reduced β-catenin signalling in migrating VSMCs, as assessed by β-galactosidase immunocytochemistry (22.3±5% vs 33.5±5%, n = 3, p<0.05). Additionally, we observed the FGF-R is essential for the anti-proliferative effect of SNC (58±12% reduction in proliferation vs 11±6% with FGFR1 inhibitor, n = 4, p<0.05). Involvement of FGFR in the anti-migratory effect of SNC is currently being investigated. In summary, SNC could have potential as a therapeutic for atherosclerosis and restenosis by reducing VSMC migration and proliferation, and its effect on these two vitally important processes is through divergent mechanisms.

C-MYB: A SURVIVAL FACTOR IN ATHEROSCLEROSIS?

K. Farrell, C. M. Holt. Cardiovascular Research Group, Core Technology Facility, University of Manchester, Manchester M13 9NT, UK

Atherosclerosis involves the proliferation and death of vascular smooth muscle cells. C-Myb …

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