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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:401.)
© 2009 American Heart Association, Inc.

Cell Biology/Signaling

Angiopoietin-2 Exocytosis Is Stimulated by Sphingosine-1-Phosphate in Human Blood and Lymphatic Endothelial Cells

Cholsoon Jang; Young Jun Koh; Nam Kyu Lim; Hyun Jung Kang; Duk Hoon Kim; Sung Kwang Park; Gyun Min Lee; Choon Ju Jeon; Gou Young Koh

From the National Research Laboratory of Vascular Biology and Department of Biological Sciences (C.J., Y.J.K., G.M.L., G.Y.K.), KAIST, Daejeon; the Biotherapeutic Division (C.J., N.K.L., H.J.K., C.J.J.), GenExel-Sein Inc, Daejeon; and the Department of Internal Medicine (D.H.K., S.K.P.), Chonbuk National University Medical School, Jeonju, Republic of Korea.

Correspondence to Gou Young Koh, National Research Laboratory for Vascular Biology, Department of Biological Sciences, KAIST, 373-1, Guseong-dong, Daejeon, 305-701, Republic of Korea. E-mail gykoh{at}kaist.ac.kr

Objective— Although diverse functions of angiopoietin-2 (Ang2) have been revealed, little is known about upstream signaling molecules regulating Ang2 exocytosis. We therefore investigated the mechanism of Ang2 exocytosis in human blood and lymphatic endothelial cells (BECs and LECs) by stimulation with sphingosine-1-phosphate (S1P).

Methods and Results— By immunostaining and ELISA analyses using our newly developed human Ang2-specific antibodies, Ang2 exocytosis from human endothelial cells was examined. Both exogenous and endogenous S1P trigger rapid Ang2 exocytosis in time- and dose-dependent manners. Intriguingly, S1P-induced Ang2 exocytosis is higher in LECs than BECs. These effects of S1P are mainly mediated by the endothelial differentiation gene receptor 1, which subsequently activates its downstream phospholipase C and intracellular calcium mobilization to trigger Ang2 exocytosis. Consistently, S1P also dramatically stimulates Ang2 exocytosis from the ECs of ex vivo–incubated blood vessels.

Conclusion— These results imply that the rapid secretion of Ang2 by exocytosis from endothelial cells is another possible mechanism underlying S1P-induced angiogenesis and inflammation.

The underlying mechanism of Ang2 exocytosis from human endothelial cells was examined by stimulation with S1P. S1P triggers rapid Ang2 exocytosis, which is mainly mediated by EDG1/phospholipase C/intracellular calcium mobilization. The rapid secretion of Ang2 by exocytosis from endothelial cells is a possible mechanism for S1P-induced angiogenesis and inflammation.

Key Words: angiogenesis • angiopoietin • endothelial differentiation gene receptor • lymphangiogenesis • Weibel-Palade bodies

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