Src 下游的 PLD1 依赖性 PKCγ激活对于病理性视网膜新生血管的形成是必需的。
PLD1-dependent PKCgamma activation downstream to Src is essential for the development of pathologic retinal neovascularization.
机构信息
Departments of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
出版信息
Blood. 2010 Aug 26;116(8):1377-85. doi: 10.1182/blood-2010-02-271478. Epub 2010 Apr 26.
Vascular endothelial growth factor (VEGF) appears to be an important mediator of pathologic retinal angiogenesis. In understanding the mechanisms of pathologic retinal neovascularization, we found that VEGF activates PLD1 in human retinal microvascular endothelial cells, and this event is dependent on Src. In addition, VEGF activates protein kinase C-gamma (PKCgamma) via Src-dependent PLD1 stimulation. Inhibition of Src, PLD1, or PKCgamma via pharmacologic, dominant negative mutant, or siRNA approaches significantly attenuated VEGF-induced human retinal microvascular endothelial cell migration, proliferation, and tube formation. Hypoxia also induced Src-PLD1-PKCgamma signaling in retina, leading to retinal neovascularization. Furthermore, siRNA-mediated down-regulation of VEGF inhibited hypoxia-induced Src-PLD1-PKCgamma activation and neovascularization. Blockade of Src-PLD1-PKCgamma signaling via the siRNA approach also suppressed hypoxia-induced retinal neovascularization. Thus, these observations demonstrate, for the first time, that Src-dependent PLD1-PKCgamma activation plays an important role in pathologic retinal angiogenesis.
血管内皮生长因子（VEGF）似乎是病理性视网膜血管生成的重要介质。在了解病理性视网膜新生血管形成的机制时，我们发现 VEGF 激活了人视网膜微血管内皮细胞中的 PLD1，而这一事件依赖于Src。此外，VEGF 通过Src 依赖性 PLD1 刺激激活蛋白激酶 C-γ（PKCγ）。通过药理学、显性负突变体或 siRNA 方法抑制 Src、PLD1 或 PKCγ，可显著减弱 VEGF 诱导的人视网膜微血管内皮细胞迁移、增殖和管形成。缺氧也诱导了视网膜中的 Src-PLD1-PKCγ信号通路，导致视网膜新生血管形成。此外，siRNA 介导的 VEGF 下调抑制了缺氧诱导的 Src-PLD1-PKCγ 激活和新生血管形成。通过 siRNA 方法阻断 Src-PLD1-PKCγ 信号通路也抑制了缺氧诱导的视网膜新生血管形成。因此，这些观察结果首次表明，Src 依赖性 PLD1-PKCγ 激活在病理性视网膜血管生成中发挥重要作用。
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