title: N-cadherin-dependent cell-cell contacts promote human saphenous vein smooth muscle cell survival.
abstract: OBJECTIVE
  Vascular smooth muscle cell (VSMC) apoptosis is thought to contribute to atherosclerotic plaque instability. Cadherin mediates calcium-dependent homophilic cell-cell contact. We studied the role of N-cadherin in VSMC apoptosis.
  
  
  RESULTS
  Human saphenous vein VSMCs were grown in agarose-coated wells to allow cadherin-mediated aggregate formation. Cell death and apoptosis were determined after disruption of cadherins using several approaches (n> or =3 per approach). Calcium removal from culture medium or addition of nonspecific cadherin antagonist peptides significantly decreased aggregate formation and increased cell death by apoptosis (34+/-6% versus 75+/-1% and 19+/-1% versus 40+/-5%, respectively; P<0.05). Specific inhibition of N-cadherin using antagonists and neutralizing antibodies similarly increased apoptosis. Supporting this, overexpression of full-length N-cadherin significantly reduced VSMC apoptosis from 44+/-10% to 20+/-3% (P<0.05), whereas abolishing N-cadherin expression by overexpression of a dominant-negative N-cadherin significantly, even in the presence of cell-matrix contacts, increased apoptosis from 9+/-2% to 50+/-1% (P<0.05). Interestingly, cell-cell contacts provided a similar degree of protection from apoptosis to cell-matrix contacts. Finally, N-cadherin-mediated cell-cell contacts initiated anti-apoptotic signaling by increasing Akt and Bad phosphorylation.
  
  
  CONCLUSIONS
  Our results indicate that VSMC survival is dependent on N-cadherin-mediated cell-cell contacts, which could be important in the context of plaque instability.
authors.affiliation: Bristol Heart Institute, Bristol Royal Infirmary, Bristol, UK.
authors.forename: Evgenia
authors.initials: E
authors.lastname: Koutsouki
authors.forename: Cressida A
authors.initials: CA
authors.lastname: Beeching
authors.forename: Sadie C
authors.initials: SC
authors.lastname: Slater
authors.forename: Orest W
authors.initials: OW
authors.lastname: Blaschuk
authors.forename: Graciela B
authors.initials: GB
authors.lastname: Sala-Newby
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: George
mesh_terms: D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology*; D015820:Cadherins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D002449:Cell Aggregation / Q000502:physiology; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000502:physiology; D015870:Gene Expression; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism; D012501:Saphenous Vein / Q000166:cytology*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000906:Antibodies; D015820:Cadherins; D002118:Calcium