FTY720 inhibits S1P-mediated endothelial healing: relationship to S1P1-receptor surface expression.
The phosphorylated derivative of the immunosuppressant FTY720 interacts with and modulates the function of sphingosine-1-phosphate (S1P)-receptors. We observed a significant reduction of endothelial surface binding of a S1P(1)-specific antibody after FTY720 treatment of 6h and longer, which was associated with a reduced healing after mechanic injury, impaired angiogenesis and enhanced adhesion molecule expression. FTY720 (5h) had no impact on the expression of S1P(1)- or S1P(3)-encoding transcripts. Notably, pre-treatment of cells with FTY720 for only 30min, which did not reduce S1P(1) surface expression, inhibited the rapid S1P- and SEW2871- (a S1P(1) agonist) induced cortical actin formation and cell migration. FTY720 was effective at concentrations as low as 5nM. FTY720 at therapeutic concentrations may be harmful by impairing important endothelial functions. Interestingly, FTY720 inhibited endothelial actin remodelling and cell migration without decreasing S1P(1) surface expression.
Krump-Konvalinkova
Vera
V
Institute for Prevention of Cardiovascular Diseases, University of Munich, Pettenkoferstrasse 9, 80336 Munich, Germany. vkrump@med.uni-muenchen.de
Chwalla
Ilona
I
Siess
Wolfgang
W
D000199:Actins / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000032:analysis / Q000378:metabolism; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008246:Lysophospholipids / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010069:Oxadiazoles / Q000494:pharmacology; D011409:Propylene Glycols / Q000494:pharmacology*; D049349:Receptors, Lysosphingolipid / Q000032:analysis / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D014945:Wound Healing / Q000187:drug effects*
D000199:Actins; D015815:Cell Adhesion Molecules; D007166:Immunosuppressive Agents; D008246:Lysophospholipids; D010069:Oxadiazoles; D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; C503964:SEW2871; D013876:Thiophenes; C060506:sphingosine 1-phosphate; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine