(A) HUVECs were serum starved for 3hrs and lysates were collected following 1μM S1P stimulation for 5min. Rac1 activity was measured by G-LISA assay and normalized to unstimulated cells for each condition (N=3, **p<0.01). (B) HUVECs were treated with IBMX and Forskolin followed by addition of 1μM S1P for 30min. Lysates were collected with 0.1M HCl, and cAMP levels were measured using a competitive immunoassay. (N=3, **p<0.01) (C and D) Following serum starvation and S1P treatment (1μM, 5min), (C) Ras activity was measured by G-LISA assay and normalized to unstimulated cells (N=3, *p<0.05). (D-E) Western blotting for ERK phosphorylation and quantification by densitometry analysis, normalized to the signal of total ERK protein respectively (N=3, **p<0.01). All significance (A-E) was determined by ANOVA with Bonferroni correction for multiple comparisons test.