Sphingosine 1-phosphate receptor regulation of N-cadherin mediates vascular stabilization.
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.
Paik
Ji-Hye
JH
Center for Vascular Biology, Department of Cell Biology, University of Connecticut Health Center, Farmington, Connecticut 06030-3501, USA.
Skoura
Athanasia
A
Chae
Sung-Suk
SS
Cowan
Ann E
AE
Han
David K
DK
Proia
Richard L
RL
Hla
Timothy
T
D000818:Animals; D001808:Blood Vessels / Q000502:physiology*; D015820:Cadherins / Q000502:physiology*; D051379:Mice; D010766:Phosphorylation; D021381:Protein Transport; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D049312:Receptors, Lysophospholipid; D015398:Signal Transduction
D015820:Cadherins; D043562:Receptors, G-Protein-Coupled; D049312:Receptors, Lysophospholipid