title: Soluble N-cadherin: A novel inhibitor of VSMC proliferation and intimal thickening.
abstract: Reoccurrence of symptoms occurs in 30-50% of coronary artery disease patients receiving vein grafts or bare-metal stents due to intimal thickening (restenosis). Restenosis is caused by vascular smooth muscle cell (VSMC) migration and proliferation. New therapeutic approaches that reduce VSMC migration and proliferation while promoting endothelial cell (EC) coverage are required. We assessed the effect of a soluble form of N-cadherin (SNC-Fc, a fusion of the extracellular portion of N-Cadherin to a mutated Fc fragment of IgG), a cell-cell junction molecule, on human saphenous VSMC proliferation and migration in vitro. We also assessed its effect on intimal thickening in a validated human ex vivo organ culture model. We observed that SNC-Fc significantly inhibited VSMC proliferation and to a lesser extent migration. The anti-proliferative effect of SNC-Fc was mediated by the interaction of SNC-Fc with the FGFR, rather than through inhibition of β-catenin signalling. SNC-Fc also significantly reduced intimal thickening by ~85% in the ex vivo organ culture model. SNC-Fc treatment inhibited proliferation of the intimal cells but did not affect migration. SNC-Fc reduced EC apoptosis, without detrimental effects on EC proliferation and migration in vitro. Importantly SNC-Fc increased EC coverage in the ex vivo model of intimal thickening. In conclusion, we suggest that SNC-Fc may have potential as an anti-proliferative therapeutic agent for reducing restenosis which has no detrimental effects on endothelial cells.
authors.affiliation: School of Clinical Sciences, Research Floor Level 7, Bristol Royal Infirmary, Upper Maudlin St, Bristol BS2 8HW, UK.
authors.forename: Cressida A
authors.initials: CA
authors.lastname: Lyon
authors.affiliation: School of Clinical Sciences, Research Floor Level 7, Bristol Royal Infirmary, Upper Maudlin St, Bristol BS2 8HW, UK.
authors.forename: Kerry S
authors.initials: KS
authors.lastname: Wadey
authors.affiliation: School of Clinical Sciences, Research Floor Level 7, Bristol Royal Infirmary, Upper Maudlin St, Bristol BS2 8HW, UK. Electronic address: s.j.george@bristol.ac.uk.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: George
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015820:Cadherins / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D023903:Coronary Restenosis / Q000517:prevention & control; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D009924:Organ Culture Techniques; D012501:Saphenous Vein / Q000166:cytology / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D017539:Tunica Intima / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism
chemical_list: D015820:Cadherins; D051176:beta Catenin
keywords: Cadherin; Endothelial; Intimal thickening; Proliferation; Smooth muscle