National Center for Food Safety and Technology, Illinois Institute of Technology, Summit Argo, Illinois, USA.
Ann N Y Acad Sci. 2010 Aug;1203:66-72. doi: 10.1111/j.1749-6632.2010.05601.x.
Vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2), a tyrosine kinase receptor, is activated by VEGF and fluid shear stress (FSS), and its downstream signaling is important in regulation of endothelial functions, such as cell migration, endothelium-dependent relaxation, and angiogenesis. Inhibition of VEGFR2 augments cigarette smoke (CS)-induced oxidative stress and inflammatory responses leading to endothelial dysfunction. CS-derived reactive oxygen/nitrogen species interact with VEGFR2, causing posttranslational modifications that render VEGFR2 inactive for downstream signaling, resulting in endothelial dysfunction. CS-mediated oxidants/carbonyl stress decreases SIRT1 levels and causes eNOS acetylation, which has ramifications in endothelial dysfunction. CS also affects endothelial cell survival pathway by disrupting VEGF- and FSS-mediated VEGFR2/PI3-kinase signaling, leading to decreased Akt phosphorylation and eNOS acetylation. We describe here the mechanisms whereby CS alters VEGF- and FSS-mediated VEGFR2-eNOS signaling, which may have implications for understanding the pathogenesis of pulmonary and cardiovascular diseases.
血管内皮生长因子受体 2（VEGFR2）是一种酪氨酸激酶受体，可被血管内皮生长因子（VEGF）和流体切应力（FSS）激活，其下游信号通路在调节内皮功能方面非常重要，如细胞迁移、内皮依赖性舒张和血管生成。VEGFR2 的抑制可增强香烟烟雾（CS）诱导的氧化应激和炎症反应，导致内皮功能障碍。CS 衍生的活性氧/氮物种与 VEGFR2 相互作用，导致翻译后修饰使 VEGFR2 无法进行下游信号转导，从而导致内皮功能障碍。CS 介导的氧化剂/羰基应激会降低 SIRT1 水平并导致 eNOS 乙酰化，这对内皮功能障碍有影响。CS 还通过破坏 VEGF 和 FSS 介导的 VEGFR2/PI3-激酶信号通路来影响内皮细胞存活途径，导致 Akt 磷酸化和 eNOS 乙酰化减少。我们在这里描述了 CS 改变 VEGF 和 FSS 介导的 VEGFR2-eNOS 信号通路的机制，这可能对理解肺部和心血管疾病的发病机制具有重要意义。
