Dismantling of cadherin-mediated cell-cell contacts modulates smooth muscle cell proliferation.
Proliferation of vascular smooth muscle cells (VSMCs) contributes to intimal thickening during atherosclerosis and restenosis. The cadherins are transmembrane proteins, which form cell-cell contacts and may regulate VSMC proliferation. In this study, N-cadherin protein concentration was significantly reduced by stimulation of proliferation with fetal calf serum (FCS) and platelet-derived growth factor-BB (PDGF-BB) in human saphenous vein VSMCs. Furthermore, overexpression of a truncated N-cadherin, which acts as a dominant-negative increased VSMC proliferation. The amount of an extracellular fragment of N-cadherin (approximately 90 kDa) in the media after 24 hours was increased by 12-fold by FCS and 11-fold by PDGF-BB, suggesting that N-cadherin levels are regulated by proteolytic shedding. Incubation with a synthetic metalloproteinase inhibitor or adenoviral overexpression of the endogenous tissue inhibitors of metalloproteinases (TIMPs) demonstrated that metalloproteinase activity was responsible in part for this proteolysis. Although total levels of beta-catenin protein were not affected, beta-catenin was translocated to the nucleus after stimulation with FCS and PDGF-BB. Our data indicates cadherin-mediated cell-cell contacts modulate proliferation in VSMCs. Furthermore, disruption of N-cadherin cell-cell contacts mediated in part by metalloproteinase activity occurs during VSMC proliferation, releasing beta-catenin and possibly inducing beta-catenin-mediated intracellular signaling.
Uglow
Elizabeth B
EB
Bristol Heart Institute, Level 7, Bristol Royal Infirmary, Bristol, BS2 8HW, UK.
Slater
Sadie
S
Sala-Newby
Graciela B
GB
Aguilera-Garcia
Concepción M
CM
Angelini
Gianni D
GD
Newby
Andrew C
AC
George
Sarah J
SJ
D000818:Animals; D000077214:Becaplermin; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002417:Cattle; D002448:Cell Adhesion / Q000502:physiology; D002450:Cell Communication / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D003470:Culture Media / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005312:Fetal Blood; D015870:Gene Expression; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009154:Mutation; D010446:Peptide Fragments / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D020574:Proto-Oncogene Proteins c-sis; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D051176:beta Catenin
C495270:CTNNB1 protein, human; D015820:Cadherins; D003470:Culture Media; D003598:Cytoskeletal Proteins; D010446:Peptide Fragments; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D019715:Tissue Inhibitor of Metalloproteinase-1; D015534:Trans-Activators; D051176:beta Catenin; D019716:Tissue Inhibitor of Metalloproteinase-2; D000077214:Becaplermin