Inhibition of N-cadherin retards smooth muscle cell migration and intimal thickening via induction of apoptosis

Cressida A Lyon, Evgenia Koutsouki, Concepcion M Aguilera, Orest W Blaschuk, Sarah Jane George

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

OBJECTIVES: Inhibition of vascular smooth muscle cell (VSMC) migration is a potential strategy for reducing intimal thickening during in-stent restenosis and vein graft failure. In this study, we examined the effect of disrupting the function of the VSMC adhesion molecule, N-cadherin, using antagonists, neutralizing antibodies, and a dominant negative, on VSMC migration and intimal thickening. Migration was assessed by the scratch-wound assay of human saphenous vein VSMCs and in a human saphenous vein ex vivo organ culture model of intimal thickening.

RESULTS: Inhibition of cadherin function using a pan-cadherin antagonist, significantly reduced migration by 53%±8% compared with the control peptide (n=3; P<.05). Furthermore, inhibition of N-cadherin function with an N-cadherin antagonist, neutralizing antibodies, and adenoviral expression of dominant negative N-cadherin (RAd dn-N-cadherin), significantly reduced migration by 31%±2%, 23%±1% and 32%±7% compared with controls, respectively (n=3; P<.05). Inhibition of cadherin function significantly increased apoptosis by between 1.5- and 3.3-fold at the wound edge. In an ex vivo model of intimal thickening, inhibition of N-cadherin function by infection of human saphenous vein segments with RAd dn-N-cadherin significantly reduced VSMC migration by 55% and increased VSMC apoptosis by 2.7-fold. As a result, intimal thickening was significantly suppressed by 54%±14%. Importantly, there was no detrimental effect of dn-N-cadherin on endothelial coverage; in fact, it was significantly increased, as was survival of cultured human saphenous vein endothelial cells.

CONCLUSIONS: Under the condition of this study, cell-cell adhesion mediated by N-cadherin regulates VSMC migration via modulation of viability. Interestingly, inhibition of N-cadherin function significantly retards intimal thickening via inhibition of VSMC migration and promotion of endothelial cell survival. We suggest that disruption of N-cadherin-mediated cell-cell contacts is a potential strategy for reducing VSMC migration and intimal thickening.

Original languageEnglish
Pages (from-to)1301-1309
Number of pages9
JournalJournal of vascular surgery
Volume52
Issue number5
Early online date14 Jul 2010
DOIs
Publication statusPublished - 1 Nov 2010

Keywords

  • Antibodies/pharmacology
  • Antigens, CD/genetics
  • Apoptosis/drug effects
  • Cadherins/antagonists & inhibitors
  • Cell Movement/drug effects
  • Cell Survival/drug effects
  • Cells, Cultured
  • Humans
  • Muscle, Smooth, Vascular/drug effects
  • Myocytes, Smooth Muscle/drug effects
  • Organ Culture Techniques
  • Peptides, Cyclic/pharmacology
  • Saphenous Vein/drug effects
  • Time Factors
  • Transfection
  • Tunica Intima/drug effects

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