Therapeutic interference with EphrinB2 signalling inhibits oxygen-induced angioproliferative retinopathy
Therapeutic interference with EphrinB2 signalling inhibits oxygen-induced angioproliferative retinopathy
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DOI：
10.1111/j.1755-3768.2009.01609.x
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发表时间：
2011-02-01
影响因子：
3.4
通讯作者：
Agostini, Hansjuergen T.
中科院分区：
文献类型：
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作者：
Ehlken, Christoph;Martin, Gottfried;Agostini, Hansjuergen T.
目的：研究在生理或病理条件下，EphrinB2（EfnB2）或EphB4是否影响视网膜血管生成。
方法：利用氧诱导的增殖性视网膜病变（OIR）小鼠模型，通过定量聚合酶链反应（qPCR）对EfnB2、EphB4、血管内皮生长因子（VEGF）、VEGFR1和VEGFR2的表达进行定量，并在EfnB2 - 和EphB4 - lacZ小鼠中进行定位。通过玻璃体内注射二聚体EfnB2以及单体或二聚体EphB4来调控血管增殖性视网膜病变。
结果：二聚体EphB4（EphB4 - Fc）和EfnB2（EfnB2 - Fc）增强了缺氧诱导的血管增殖性视网膜病变，但不影响生理血管生成。单体EphB4（sEphB4）减少了血管生成。EfnB2的信使RNA（mRNA）水平在高氧阶段（P7 - P12）显著升高，而EphB4、VEGF、VEGFR1和VEGFR2在P14（由相对缺氧导致的形态学可见的血管增殖开始时）表达显著增加，最多可达五倍。
结论：ephrin/Eph系统参与血管增殖性视网膜病变。分别使用EfnB2 - Fc和EphB4 - Fc刺激EphB4和EfnB2信号传导，增强了缺氧诱导的血管生成。相反，sEphB4抑制缺氧诱导的血管生成。因此，通过EphB4（正向）和EfnB2（反向）的信号传导均可增强血管生成。EphB4和EfnB2表达动力学的差异表明它们调控两种不同的信号通路，并以不同方式受到调节。sEphB4可能是一种用于抗血管生成治疗的有用药物。
Purpose: To investigate whether EphrinB2 (EfnB2) or EphB4 influence retinal angiogenesis under physiological or pathological conditions.Methods: Using the mouse model of oxygen-induced proliferative retinopathy (OIR), the expression of EfnB2, EphB4, vascular endothelial growth factor (VEGF), VEGFR1 and VEGFR2 was quantified by quantitative polymerase chain reaction (qPCR) and localized in EfnB2- and EphB4-lacZ mice. Angio-proliferative retinopathy was manipulated by intravitreal injection of dimeric EfnB2 and monomeric or dimeric EphB4.Results: Dimeric EphB4 (EphB4-Fc) and EfnB2 (EfnB2-Fc) enhanced hypoxia-induced angioproliferative retinopathy but not physiological angiogenesis. Monomeric EphB4 (sEphB4) reduced angiogenesis. The messenger RNA (mRNA) level of EfnB2 increased significantly in the hyperoxic phase (P7-P12), while EphB4, VEGF, VEGFR1 and VEGFR2 showed a significant - up to fivefold - increased expression at P14, the start of morphologically visible vasoproliferation caused by relative hypoxia.Conclusion: The ephrin/Eph system is involved in angioproliferative retinopathy. Stimulation of EphB4 and EfnB2 signalling using EfnB2-Fc and EphB4-Fc, respectively, enhanced hypoxia-induced angiogenesis. In contrast, sEphB4 inhibited hypoxia-induced angiogenesis. Therefore, angiogenesis is enhanced by signalling through both EphB4 (forward) and EfnB2 (reverse). The distinction in the expression kinetics of EphB4 and EfnB2 indicates that they govern two different signalling pathways and are regulated in diverse ways. sEphB4 might be a useful drug for antiangiogenic therapy.