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RESEARCH PAPER
1 Center for Vascular Biology, Department of Cell Biology, and 2 Center for Biomedical Imaging Technology, University of Connecticut Health Center, Farmington, Connecticut 06030-3501, USA; 3 Genetics of Disease and Development Branch, National Institutes of Diabetes, Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, Maryland 20892, USA
Vascular stabilization, a process by which nascent vessels are invested with mural cells, is important in angiogenesis. Here we describe the molecular basis of vascular stabilization regulated by sphingosine 1-phosphate (S1P), a platelet-derived lipid mediator. S1P1 receptor-dependent cell-surface trafficking and activation of the cell-cell adhesion molecule N-cadherin is essential for interactions between endothelial and mural cells. Endothelial cell S1P1/Gi/Rac pathway induces microtubule polymerization, resulting in trafficking of N-cadherin to polarized plasma membrane domains. S1P treatment modulated the phosphorylation of N-cadherin as well as p120-catenin and induced the formation of cadherin/catenin/actin complexes containing novel regulatory and trafficking factors. The net result of endothelial cell S1P1 receptor activation is the proper trafficking and strengthening of N-cadherin-dependent cell-cell adhesion with mural cells. Perturbation of N-cadherin expression with small interfering RNA profoundly attenuated vascular stabilization in vitro and in vivo. S1P-induced trafficking and activation of N-cadherin provides a novel mechanism for the stabilization of nascent blood vessels by mural cells and may be exploited to control angiogenesis and vascular diseases.
[Keywords: sphingosine 1-phosphate; cadherin; angiogenesis; vascular stabilization; endothelial cells; pericytes]
Received June 2, 2004; revised version accepted August 11, 2004.
Article published online ahead of print. Article and publication date are at http://www.genesdev.org/cgi/doi/10.1101/gad.1227804.
4 Corresponding author.
E-MAIL hla{at}nso2.uchc.edu; FAX (860) 679-1201.
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