Hypoxia up‐regulates expression of Eph receptors and ephrins in mouse skin
Hypoxia up‐regulates expression of Eph receptors and ephrins in mouse skin
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DOI：
10.1096/fj.04-3647fje
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发表时间：
2005-10
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影响因子：
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通讯作者：
Meri M. Vihanto;Jan A. Plock;Dominique Erni;Brigitte M. Frey;Felix J. Frey;U. Huynh-Do
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文献类型：
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作者：
Meri M. Vihanto;Jan A. Plock;Dominique Erni;Brigitte M. Frey;Felix J. Frey;U. Huynh-Do
Eph受体酪氨酸激酶及其配体（ephrin）在胚胎脉管系统发育过程中起着关键作用；然而，它们在成人血管生成中的作用和调控仍有待明确。受体和配体已被证明在多种肿瘤中上调。为了验证缺氧是Ephs/ephrins表达的重要调节因子这一假说，我们建立了小鼠缺氧皮瓣模型。通过连续测量部分皮肤氧张力、监测组织乳酸/丙酮酸比值、缺氧诱导因子- 1α (HLF - 1α)诱导的时间过程，以及免疫荧光法在缺氧皮瓣中定位稳定的HIF - 1α，我们证明了我们的模型真正地代表了局部皮肤缺氧。我们的实验表明，缺氧不仅上调HIF - 1α和血管内皮生长因子（VEGF）的表达，还上调皮肤中A和B亚类的Ephs和ephrins的表达。此外，我们发现在Hep3B和PC‐3细胞中，缺氧诱导的HIF‐1α上调被小干扰RNA介导的HIF‐1α下调所抵消。这些新发现揭示了这种多功能受体/配体家族在成人血管生成中的作用。此外，我们的模型为分析基因靶向小鼠新生血管的不同机制提供了相当大的潜力。
Eph receptor tyrosine kinases and their ligands (ephrins) are key players during the development of the embryonic vasculature; however, their role and regulation in adult angiogenesis remain to be defined. Both receptors and ligands have been shown to be up‐regulated in a variety of tumors. To address the hypothesis that hypoxia is an important regulator of Ephs/ephrins expression, we developed a mouse skin flap model of hypoxia. We demonstrate that our model truly represents segmental skin hypoxia by applying four independent methods: continuous measurement of partial cutaneous oxygen tension, monitoring of tissue lactate/pyruvate ratio, time course of hypoxia‐inducible factor‐1α (HLF‐1α) induction, and localization of stabilized HIF‐1α by immunofluorescence in the hypoxic skin flap. Our experiments indicate that hypoxia up‐regulates not only HIF‐1α and vascular endothelial growth factor (VEGF) expression, but also Ephs and ephrins of both A and B subclasses in the skin. In addition, we show that in Hep3B and PC‐3 cells, the hypoxia‐induced up‐regulation of Ephs and ephrins is abrogated by small interfering RNA‐mediated down‐regulation of HIF‐1α. These novel findings shed light on the role of this versatile receptor/ligand family in adult angiogenesis. Furthermore, our model offers considerable potential for analyzing distinct mechanisms of neovascularization in gene‐targeted mice.