Interrated research on the physiological role ofbioactive sphingosine-1-phosphate and Edg receptors by using genetically engineered maice.

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We investigated physiological and pathophysiological roles of sphingosine-l-phosphate (S1P) and its receptors in the cardiovascular system and tumor progression. Slp exerts its pleiotropic effects through acting on the Edg family receptors. The mice that is null for the S1P receptor Edg5 exhibits hypotension compared with wild type littermates. The Edg5-knockout (Edg5-KO) mice showed similar extents of pressor responses to angiotensin II, ACTH, and the nitric oxide synthase inhibitor L-NAME, as the wild type mice. In the murine hindlimb ischemic model due to femoral artery ligation, daily local intramuscular injection into the ischemic limb promoted the recovery of the blood flow with a concomitant increase in the capillary density in the ischemic limb. The PLGA-based slow-releasing S1P that we invented was also effective in stimulating the blood flow recovery. We also found that the mice transgenic for the S1P-synthesizing enzyme sphingosine kinase-1 showed stimulated recovery in the post-ischemic blood flow. In the in vitro capillary-like tube formation assay, the anti-migratory receptor Edg5 inhibited tube formation, and the blockade of Edg5 stimulated tube formation. Thus, Edg5 is likely anti-angiogenic receptor. Edgl is expressed in cardiomyocytes, however, its role is not known. We found that the mice transgenic for Edgl exhibited cardiac hypertrophy, which was prevented by an AT1 receptor antagonist. In the murine tail vein injection model, an Edgl agonist stimulated lung metastasis of B16 melanoma cells probably through acting on Edgl in the host tissues. These results collectively indicate that S1P-Edg system plays important roles in the cardiovascular homeostasis and the cardiovascular and tumor pathophysiology, and suggest potential usefulness of novel therapeutic strategy to target the S1P-Edg system.