This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 103/4/405    most recent CIRCRESAHA.108.175307v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sabatini, P. J.B. Articles by Langille, B. L. Search for Related Content PubMed PubMed Citation Articles by Sabatini, P. J.B. Articles by Langille, B. L. Pubmed/NCBI databases Gene GEO Profiles HomoloGene Protein UniGene Substance via MeSH Related Collections Restenosis Cell biology/structural biology Smooth muscle proliferation and differentiation

(Circulation Research. 2008;103:405.)
© 2008 American Heart Association, Inc.

Cellular Biology

Homotypic and Endothelial Cell Adhesions via N-Cadherin Determine Polarity and Regulate Migration of Vascular Smooth Muscle Cells

Peter J.B. Sabatini, Ming Zhang, Rosalind Silverman-Gavrila, Michelle P. Bendeck, B. Lowell Langille

From the Department of Laboratory Medicine and Pathobiology (P.J.B.S., M.P.B., B.L.L.), University of Toronto; and Division of Cell and Molecular Biology (P.J.B.S., M.Z., R.S.-G., B.L.L.), Toronto General Research Institute, University Health Network, Canada.

Correspondence to B. Lowell Langille, MaRS Centre, Toronto Medical Discoveries Tower, 101 College St, 3-308, Toronto, ON, Canada M5G 1L7. E-mail langille{at}uhnres.utoronto.ca

Migration of smooth muscle cells from the arterial media to the intima is central to several vascular pathologies including restenosis. This study demonstrates that, like directional migration of other cells, smooth muscle migration is accompanied by a dramatic, polarized reorganization of the cell cytoskeleton that is accompanied by activation of the Rho GTPase Cdc42 and inactivation of glycogen synthase kinase-3β. We also show, for the first time, that signals generated at the posterior–lateral aspects of wound edge cells by the cell–cell adhesion molecule N-cadherin are required for polarization and rapid migration of vascular smooth muscle. Importantly, when a cohort of migrating smooth muscle cells encounter CHO cells or the A10 smooth muscle cell line, neither of which expresses N-cadherin, polarity is only slightly suppressed. However, when smooth muscle cells encounter stably transfected, N-cadherin–expressing A10 cells or (N-cadherin–expressing) vascular endothelium, they rapidly lose their polarized phenotype. The latter finding indicates that endothelial signaling to innermost smooth muscle cells via N-cadherin may be critical to normal vessel wall stability. We infer that asymmetrical distribution of N-cadherin is necessary for the establishment of cell polarity during migration and that N-cadherin ligation is highly effective in abrogating polarized migration. Finally, we showed that endothelial cell polarity does not depend on N-cadherin; therefore, this molecule may be an attractive target for therapies to prevent restenosis without suppressing endothelial repair and risking late thrombosis.

Key Words: smooth muscle cell • migration • N-cadherin • polarity • restenosis

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