© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
Downregulation of N-cadherin in the neointima stimulates migration of smooth muscle cells by RhoA deactivation
aMedical Clinic I, University Hospital Aachen, Pauwelsstr 30, 52074 Aachen, Germany
bInstitute of Pathology, University Regensburg, 93053 Regensburg, Germany
cInterdisciplinary Centre for Clinical Research in Biomaterials and Tissue–Material–Interaction in Implants "BIOMAT", University Hospital Aachen, Aachen, Germany
dDepartment for Cardiothoracic Surgery, University Hospital Aachen, Aachen, Germany
eDepartment of Molecular Cardiovascular Research, University Hospital Aachen, Aachen, Germany
* Corresponding author. Tel.: +49-241-8089300; fax: +49-2421-959262. Email address: ruediger.blindt{at}post.rwth-aachen.de
Objective: The aim of the study was to analyze whether cadherin- and Rho-family GTPases-mediated dynamic rearrangement of cell–cell adhesion play an important role during human arterial smooth muscle cell (haSMC) migration. Methods: Expression patterns of N-cadherin and β-catenin were analyzed in a domestic pig restenosis model after 14, 28, and 90 days as well as in quiescent and migratory haSMCs in vitro. N-cadherin expression was upregulated by transient sense; downregulation was induced by antisense transfection. For functional inhibition, antibody GC-4 was used. Cell migration was quantified using Boyden chamber assays. Regulation of RhoA GTPase was tested by assessment of RhoA activity. Results: In vivo analysis of N-cadherin expression in a porcine restenosis model revealed downregulation in the neointima after 14 days. After 28 days, N-cadherin expression was slightly restored, while after 90 days, no difference between medial and neointimal expression was detectable. β-Catenin levels remained unchanged during the whole period. According to the in vivo situation, N-cadherin was significantly downregulated in migratory haSMCs compared to quiescent cells in vitro. After N-cadherin overexpression, haSMC migration was reduced by 87% (P<0.001). By contrast, inhibition of N-cadherin in quiescent haSMCs by GC-4 increased the migratory potential by 87% (P<0.01). In haSMCs overexpressing N-cadherin, a significant upregulation of RhoA activity was demonstrated, while RhoA activity was blocked by GC-4. Conclusions: These results indicate that the regulation of haSMC attachment by N-cadherins is essential for haSMC migration. Modification of N-cadherin expression and activity induces RhoA signaling with relevance for the reorganization of the actin cytoskeleton.
KEYWORDS Adhesion molecules; Restenosis; Smooth muscle cells
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