P140	Sphingosine-1-phosphate receptor S1P1 is a key regulator of endothelial cell function.
1V.Krump-Konvalinkova, 2S.Yasuda, 1T.Rubic, 1W.Erl, 1C.Vosseler, 3C.J.Kirkpatrick, 2G.Tigyi, 1W.Siess
1Institute for Prophylaxis of Cardiovascular Diseases-Ludwig Maximilian University Munich, Munich, DE; 2University of Tennessee, Memphis, US; 3Institute of Pathology-University of Mainz, Mainz, DE.

Sphingosine 1-phosphate (S1P) is a bioactive phospholipid acting both as a ligand for the G-protein coupled receptors S1P1-5 and as a second messenger. To study the function of S1P1 in endothelial cells we permanently reduced expression of S1P1 by RNA interference in human endothelial cell lines AS-M.5 and ISO-HAS.1. Stable silencing of S1P1 to less than 20% of control demonstrated the involvement of S1P1 in key functions of human endothelial cells. The S1P1-knock-down clones manifested a distinct morphology, showed neither formation actin ruffles in response to S1P nor an angiogenic reaction, and showed an increased sensitivity to oxidant stress-mediated injury. Furthermore, S1P1 silencing decreased the expression of the platelet endothelial cell adhesion molecule-1 and VE-cadherin and abolished the induction of E-selectin expression with lipopolysaccharide or tumor necrosis factor-α. Microarray analysis of gene expression revealed downregulation of many endothelial specific transcripts after S1P1-silencing as well as new S1P1-dependent gene targets. Our results demonstrate that S1P1 is critical for endothelial gene expression and important for many endothelial cell functions.

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