Vascular endothelial growth factor induces rapid phosphorylation of tight junction proteins occludin and zonula occluden 1 - A potential mechanism for vascular permeability in diabetic retinopathy and tumors
Vascular endothelial growth factor induces rapid phosphorylation of tight junction proteins occludin and zonula occluden 1 - A potential mechanism for vascular permeability in diabetic retinopathy and tumors
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DOI：
10.1074/jbc.274.33.23463
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发表时间：
1999-08-13
影响因子：
4.8
通讯作者：
Gardner, TW
中科院分区：
文献类型：
--
作者：
Antonetti, DA;Barber, AJ;Gardner, TW
血管内皮生长因子 (VEGF) 可能在调节血管通透性方面发挥生理作用，并有助于糖尿病视网膜病变的病理生理学以及肿瘤的发展。我们着手确定 VEGF 调节大鼠细胞旁通透性的机制。眼内注射 VEGF 引起 occludin 的翻译后修饰，由凝胶从 60 kDa 变为 62 kDa 确定。该事件在注射后 15 分钟开始，并在 45 分钟时达到最大。碱性磷酸酶处理表明这种修饰是由 occludin 磷酸化的变化引起的。此外，提取的 occludin 数量在同一时间范围内增加了一倍。在 VEGF 刺激后培养的视网膜内皮细胞中重现了 occludin 的磷酸化和增加的提取。本文提供的数据首次证明了在内皮通透性增加的条件下这种跨膜蛋白的磷酸化发生了变化。此外，眼内注射 VEGF 早在 15 分钟就引起 ZO-1 的酪氨酸磷酸化，并在 90 分钟后磷酸化增加了 2 倍。总之，VEGF 迅速增加 occludin 磷酸化以及 ZO-1 的酪氨酸磷酸化，occludin 和 ZO-1 的磷酸化可能有助于调节内皮细胞旁细胞通透性。
Vascular endothelial growth factor (VEGF) may have a physiologic role in regulating vessel permeability and contributes to the pathophysiology of diabetic retinopathy as well as tumor development. We set out to ascertain the mechanism by which VEGF regulates paracellular permeability in rats. Intra ocular injection of VEGF caused a post-translational modification of occludin as determined by a gel shift from 60 to 62 kDa. This event began by 15 min post-injection and was maximal by 45 min. Alkaline phosphatase treatment revealed this modification was caused by a change in occludin phosphorylation, In addition, the quantity of extracted occludin increased a-fold in the same time frame, The phosphorylation and increased extraction of occludin was recapitulated in retinal endothelial cells in culture after VEGF stimulation. The data presented herein are the first demonstration of a change in the phosphorylation of this transmembrane protein under conditions of increased endothelial permeability, In addition, intraocular injection of VEGF also caused tyrosine phosphorylation of ZO-1 as early as 15 min and increased phosphorylation ii-fold after 90 min. In conclusion, VEGF rapidly increases occludin phosphorylation as well as the tyrosine phosphorylation of ZO-1, Phosphorylation of occludin and ZO-1 likely contribute to regulated endothelial paracellular permeability.