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Y. Hata, K. Fujisawa, Y. Sassa, Y. Nakamura, T. Ishibashi; Inhibitory Effects and Mechanisms on the Proliferation of Vascular Endothelial Cells by Ephirin-B2 . Invest. Ophthalmol. Vis. Sci. 2003;44(13):2883.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose:The Eph receptor tyrosine kinase family is a new class of receptor tyrosine kinases, and its role in angiogenesis is just beginning to emerge. Recent study reported that interaction between ephrinB2 and EphB4 in endothelial cells at the arterial-venous capillary interface is critical for proper embryonic capillary morphogenesis. However, the intracellular downstream signaling of ephrinB2-EphB4 in vascular endothelial cells is not fully clarified. We investigated the effect of both ephrinB2 and EphB4 on growth factor–induced endothelial cell proliferation and signaling.Methods:The effect of ephrinB2 , EphB4 or ephrinB2+EphB4 on vascular endothelial growth factor (VEGF)-induced proliferation of human aortic endothelial cells (HAoEC) were assessed by [3H]-thymidine incorporation. We next addressed the effect of ephrinB2 or EphB4 on VEGF-induced VEGFR2/KDR phosphorylation by immunoprecipitation and western blotting. We also investigated whether ephrinB2 or EphB4 suppressed VEGF-induced p44/p42 mitogen-activated protein kinase (MAPK) phosphorylation by western blotting.Results:Although ephrinB2 significantly reduced VEGF-dependent proliferation of HAoEC, EphB4 showed no apparent effect. Moreover, EphB4 diminished the inhibitory effect of ephrinB2 on the proliferation of HaoEC. Pretreatment of HaoEC with ephrinB2 or EphB4 did not affect VEGF-dependent phosphorylation of VEGFR2/KDR. However, ephrinB2 but not EphB4 significantly suppresed VEGF-induced phosphorylation of p44/p42 MAPK.Conclusions:From these results, we propose that ephrinB2 cannot suppress VEGF-induced phosphorylation of VEGFR2/KDR but suppress the p44/p42MAPK phopshorylation, which is one of the common participants in the signal transduction pathway initiated by VEGF. Although ephrinB2-EphB4 signaling is known to be bi-directional, EphB4 cannot alert either endothelial cell proliferation or MAPK phosphorylation. EphrinB2 appears to be an inhibitory regulator of angiogenesis through p44/p42 MAPK pathway at least in part.
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