Monaghan-Benson Elizabeth, Burridge Keith
Department of Cell and Developmental Biology and Lineberger Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599-7295, USA.
J Biol Chem. 2009 Sep 18;284(38):25602-11. doi: 10.1074/jbc.M109.009894. Epub 2009 Jul 26.
Vascular permeability is a complex process involving the coordinated regulation of multiple signaling pathways in the endothelial cell. It has long been documented that vascular endothelial growth factor (VEGF) greatly enhances microvascular permeability; however, the molecular mechanisms controlling VEGF-induced permeability remain unknown. Treatment of microvascular endothelial cells with VEGF led to an increase in reactive oxygen species (ROS) production. ROS are required for VEGF-induced permeability as treatment with the free radical scavenger, N-acetylcysteine, inhibited this effect. Additionally, treatment with VEGF caused ROS-dependent tyrosine phosphorylation of both vascular-endothelial (VE)-cadherin and beta-catenin. Rac1 was required for the VEGF-induced increase in permeability and adherens junction protein phosphorylation. Knockdown of Rac1 inhibited VEGF-induced ROS production consistent with Rac lying upstream of ROS in this pathway. Collectively, these data suggest that VEGF leads to a Rac-mediated generation of ROS, which, in turn, elevates the tyrosine phosphorylation of VE-cadherin and beta-catenin, ultimately regulating adherens junction integrity.
血管通透性是一个复杂的过程，涉及内皮细胞中多种信号通路的协同调节。长期以来，有文献记载血管内皮生长因子（VEGF）可显著增强微血管通透性；然而，控制VEGF诱导的通透性的分子机制仍不清楚。用VEGF处理微血管内皮细胞会导致活性氧（ROS）生成增加。ROS是VEGF诱导通透性所必需的，因为用自由基清除剂N-乙酰半胱氨酸处理可抑制这种效应。此外，用VEGF处理会导致血管内皮（VE）-钙黏蛋白和β-连环蛋白的ROS依赖性酪氨酸磷酸化。Rac1是VEGF诱导的通透性增加和黏附连接蛋白磷酸化所必需的。敲低Rac1可抑制VEGF诱导的ROS生成，这与Rac在该通路中位于ROS上游一致。总体而言，这些数据表明VEGF导致Rac介导的ROS生成，进而提高VE-钙黏蛋白和β-连环蛋白的酪氨酸磷酸化，最终调节黏附连接的完整性。
