Premium
Sphingosine‐1‐phosphate and S1P Receptors in Angiogenesis
Author(s) -
Hla Timothy
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a20-a
Subject(s) - microbiology and biotechnology , s1pr1 , sphingosine 1 phosphate , angiogenesis , mural cell , biology , pericyte , receptor , sphingosine , vascular permeability , endothelial stem cell , signal transduction , vascular endothelial growth factor a , vascular endothelial growth factor , cancer research , endocrinology , biochemistry , in vitro , vegf receptors
Sphingosine 1‐phosphate (S1P) acts in a pleiotropic manner by binding to and signaling via the S1Pn (n=1–5) family of G‐protein‐coupled receptors. Recent data shows that S1P plays a major regulatory role in blood vessel development and immune cell trafficking under physiological conditions. Knock‐out of the S1p1 gene in the mouse suggested that signaling of this receptor in endothelial cells is essential for blood vessel stabilization during embryonic development. We recent uncovered the molecular mechanism of this phenomenon. Signaling of S1P1 in endothelial cells induces the trafficking of the cell‐cell adhesion molecule N‐cadherin to polarized microdomains on the endothelial cells. In addition, N‐cadherin forms a complex with catenins and actin as well as other regulatory factors and is phosphorylated resulting in strengthening of cell‐cell junctions between endothelial cells and mural (pericytes and vascular smooth muscle) cells. This allows for proper stabilization of developing blood vessels. An S1P agonist, FTY720, is undergoing clinical trials as an immunosuppressant. We recently showed that FTY720 is phosphorylated by sphingosine kinase‐2 and acts as a potent inhibitor of VEGF‐induced vascular permeability in vivo. S1P receptor agonism may have utility in the control of vascular permeability in the adult. The S1P1 receptor is strongly induced in tumor vessels in the adult. In addition, suppression of its expression by local injection of siRNA in vivo, resulted in decreased microvessel density, decreased vascular stabilization (pericyte coverage) and attenuated tumor growth. Thus, S1P1 receptor may play a critical role in tumor angiogenesis. These data suggest that modulation of S1P signaling in the vascular system may provide a new way of regulating angiogenesis and vascular formation.