Syndecan-1 up-regulated by ephrinB2/EphB4 plays dual roles in inflammatory angiogenesis.
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.
Yuan
Kuo
K
Institute of Medical Sciences, Tzu Chi University, No. 701, Jung-Yang Rd, Section 3, Hualien, Taiwan 970.
Hong
Tse-Ming
TM
Chen
Jeremy J W
JJ
Tsai
Wan Hua
WH
Lin
Ming T
MT
D000818:Animals; D004336:Drug Antagonism; D004730:Endothelium, Vascular / Q000737:chemistry / Q000166:cytology; D036388:Ephrin-B2 / Q000378:metabolism / Q000502:physiology*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D020869:Gene Expression Profiling / Q000379:methods; D005966:Glucuronidase / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000209:etiology*; D008264:Macrophages / Q000737:chemistry; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009389:Neovascularization, Pathologic / Q000209:etiology*; D011499:Protein Processing, Post-Translational; D011509:Proteoglycans / Q000235:genetics* / Q000378:metabolism; D036224:Receptor, EphB4 / Q000378:metabolism / Q000502:physiology*; D053668:Syndecan-1; D053667:Syndecans; D015854:Up-Regulation / Q000502:physiology*; D014699:Venules; D014945:Wound Healing; D000099175:Heparanase
D036388:Ephrin-B2; D016222:Fibroblast Growth Factor 2; D005966:Glucuronidase; D008562:Membrane Glycoproteins; D011509:Proteoglycans; D036224:Receptor, EphB4; D053668:Syndecan-1; D053667:Syndecans; D000099175:Heparanase; C508241:SDC1 protein, human; C508242:Sdc1 protein, mouse