N-cadherin-dependent cell-cell contacts promote human saphenous vein smooth muscle cell survival

Evgenia Koutsouki, Cressida A Beeching, Sadie C Slater, Orest W Blaschuk, Graciela B Sala-Newby, Sarah J George

Research output: Contribution to journalArticlepeer-review

49 Citations (Scopus)

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.

METHODS AND 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.

Original languageEnglish
Pages (from-to)982-8
Number of pages7
JournalArteriosclerosis, thrombosis, and vascular biology
Volume25
Issue number5
DOIs
Publication statusPublished - May 2005

Keywords

  • Antibodies/pharmacology
  • Apoptosis/physiology
  • Atherosclerosis/metabolism
  • Cadherins/genetics
  • Calcium/metabolism
  • Cell Aggregation/physiology
  • Cell Communication/drug effects
  • Cell Survival/physiology
  • Cells, Cultured
  • Extracellular Matrix/physiology
  • Gene Expression
  • Humans
  • Muscle, Smooth, Vascular/cytology
  • Saphenous Vein/cytology
  • Signal Transduction/physiology

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