on March 17, 2005
Published online before print March 17, 2005, doi: 10.1161/01.ATV.0000163183.27658.4b
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Submitted on July 29, 2004
Accepted on March 3, 2005
N-Cadherin-Dependent Cell-Cell Contacts Promote Human Saphenous Vein Smooth Muscle Cell Survival
Evgenia Koutsouki ;
From Bristol Heart Institute (E.K., C.A.B., S.C.S., G.B.-N., S.J.G.), Bristol Royal Infirmary, Bristol, UK; Adherex Technologies Inc (O.W.B.), Ottawa, Ontario, Canada; and the Division of Urology (O.W.B.), Department of Surgery, McGill University, Montreal, Quebec, Canada.
* To whom correspondence should be addressed. E-mail: s.j.george{at}bris.ac.uk.
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
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.
Key words: apoptosis • atherosclerosis • N-cadherin • smooth muscle
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