Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:108-114
doi: 10.1161/hq0102.101843
doi: 10.1161/hq0102.101843
© 2002 American Heart Association, Inc.
Vascular Biology |
Involvement of Endothelial Nitric Oxide in Sphingosine-1-Phosphate–Induced Angiogenesis
From the Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine (Y.R., K.-i.H., S.K., M.O., T.T., N.I., M.Y.), and the Division of Diabetes, Digestive and Kidney Diseases, Department of Clinical Molecular Medicine (W.O.), Kobe University Graduate School of Medicine, Kobe, Japan.
Correspondence to Yoshiyuki Rikitake, MD, PhD, Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan. E-mail rikitake{at}med.kobe-u.ac.jp
Nitric oxide (NO) has been implicated as a critical signaling molecule of angiogenesis. Recently, sphingosine-1-phosphate (S1P) has emerged as a mediator of angiogenesis, and S1P-induced NO synthesis in endothelial cells (ECs) has been reported. To analyze the signaling pathways involved in S1P-induced angiogenesis and clarify the role of NO in this process, we performed in vivo and in vitro angiogenesis assays. S1P activated the phosphatidylinositol-3-kinase (PI3K)/Akt/endothelial NO synthase (eNOS) pathway in ECs, since S1P-stimulated eNOS phosphorylation and NO production were blocked by inhibition of activities of PI3K and Akt. S1P increased capillary ingrowth into subcutaneously implanted Matrigel plugs in mice, and the effect of S1P was significantly reduced in mice that received NG-nitro- L-arginine methyl ester (L-NAME), an inhibitor of NOS. S1P stimulated EC migration and tube formation on Matrigel, which processes were significantly decreased by inhibition of activities of PI3K, Akt, or eNOS, whereas treatment with LY294002, a PI3K inhibitor, but not L-NAME, inhibited EC viability and proliferation. Thus, our results demonstrate the crucial role of NO in S1P-induced angiogenesis in vivo and in vitro and suggest the divergent roles of NO in the S1P-induced angiogenic response.
Key Words: angiogenesis • growth substances • signal transduction
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