Published online before print March 17, 2005, doi: 10.1161/01.ATV.0000163183.27658.4b
© 2005 American Heart Association, Inc.
Vascular Biology |
N-Cadherin–Dependent Cell–Cell Contacts Promote Human Saphenous Vein Smooth Muscle Cell Survival
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.
Correspondence to Dr Sarah Jane George, Bristol Heart Institute, Level 7, Bristol Royal Infirmary, Bristol, BS2 8HW, UK. 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.
We investigated the role of N-cadherin, a transmembrane protein that mediates cell–cell contacts, in VSMC survival. Inhibition of N-cadherin significantly decreased cell–cell contact and survival. Conversely, overexpression of N-cadherin significantly decreased VSMC apoptosis. We suggest that N-cadherin promotes VSMC survival by initiating survival signals via phosphorylation of Akt and Bad.
Key Words: apoptosis • atherosclerosis • N-cadherin • smooth muscle
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