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Blood, 15 August 2004, Vol. 104, No. 4, pp. 1025-1033.
Prepublished online as a Blood First Edition Paper on May 4, 2004; DOI 10.1182/blood-2003-09-3334.


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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY

Syndecan-1 up-regulated by ephrinB2/EphB4 plays dual roles in inflammatory angiogenesis

Kuo Yuan, Tse-Ming Hong, Jeremy J. W. Chen, Wan Hua Tsai, and Ming T. Lin

From the Periodontics Division, Department of Dentistry, National Cheng Kung University Hospital, Tainan, Taiwan; School of Pharmacy, National Taiwan University College of Medicine, Taipei, Taiwan; Institute of Biomedical Sciences and Molecular Biology, National Chung Hsing University, Taichung, Taiwan; and Department of Biochemistry and Institute of Basic Medical Sciences, Medical School, National Cheng Kung University, Tainan, Taiwan.

EphrinB2 and EphB4, its cognate receptor, are important in the vascular development of the mouse embryo. Their roles in human inflammatory angiogenesis, however, are not well understood. By examining hyperinflammatory lesions, we saw that ephrinB2 was predominantly expressed in macrophage-like cells and EphB4 in small venules. Because macrophages usually transmigrate through postcapillary venules during inflammation, we wanted to explore the downstream effects of EphB4 after binding to ephrinB2. By using cDNA microarray technique and following reverse transcriptase–polymerase chain reaction (RT-PCR), we found that syntenin and syndecan-1 were up-regulated in EphB4-positive endothelial cells dose dependently and time dependently after stimulation with preclustered ephrinB2. In vitro, ephrinB2 suppressed the angiogenic effects of basic fibroblast growth factor (bFGF) on EphB4-positive endothelial cells, partially due to syndecan-1's competition with fibroblast growth factor receptor (FGFR) for bFGF. However, ephrinB2 exhibited angiogenic effects in vivo, possibly due to an inflammation-associated enzyme—heparanase. The enzymes could convert the inhibitory effect of ephrinB2 on EphB4-positive endothelial cells to an activating effect by removing poorly sulfated side chains of up-regulated syndecan-1 ectodomain. Depending on the presence of heparanases, the roles of syndecan-1 may be opposite in different physiological settings.


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