Diagnostic & Molecular Medicine Health Care Group, VA Medical Center, and Departments of Pathology and Pharmacology, University of California-Irvine, Long Beach, CA 90822, USA.
Biochem Biophys Res Commun. 2010 Sep 3;399(4):613-6. doi: 10.1016/j.bbrc.2010.07.124. Epub 2010 Aug 1.
The effects of VEGF on endothelial cells are mediated by different intracellular signaling cascades (e.g., Erk1/2, Akt, Src). VEGF plays a recently recognized role in ulcerative colitis (UC) pathogenesis, mostly by increasing vascular permeability and promoting the infiltration of inflammatory cells. We hypothesized that the excessive activation of signal transduction pathways, which is responsible for VEGF/VEGFR-2-mediated endothelial permeability (Src, Akt), is a new element in the pathogenesis of chronic UC. We demonstrated increased expression of pro-angiogenic growth factor VEGF and its receptor VEGFR-2 in colonic tissue during acute 6% iodoacetamide-induced UC in rats and chronic spontaneously developed UC in IL-10 knockout mice (IL-10 KO). Development of acute 6% iodoacetamide-induced UC in rats was accompanied by activation of Erk1/2 and Src kinase, while expression of total proteins Erk1/2 and Src was unchanged. During chronic colitis phosphorylation (i.e., activation) of Erk1/2 was significantly decreased in IL-10 KO mice vs. wild-type mice. Levels of total Erk1/2 proteins were unchanged, but the expression of total Src protein as well as its phosphorylated form was significantly increased in IL-10 KO vs. wild-type mice. There were no changes in total Akt proteins, while levels of activated Akt (pAkt) were slightly increased in IL-10 KO vs. wild-type mice. We conclude that VEGF/VEGFR-2-associated signal transduction pathways, that mediate increased vascular permeability (Src, Akt), might play a central role in perpetuation of chronic experimental UC.
VEGF 对内皮细胞的作用是通过不同的细胞内信号级联（例如 Erk1/2、Akt、Src）介导的。VEGF 在溃疡性结肠炎（UC）发病机制中起着最近被认识到的作用，主要通过增加血管通透性和促进炎症细胞浸润。我们假设，负责 VEGF/VEGFR-2 介导的内皮通透性的信号转导途径的过度激活（Src、Akt）是慢性 UC 发病机制中的一个新元素。我们证明了在大鼠急性 6%碘乙酰胺诱导的 UC 和 IL-10 敲除小鼠（IL-10 KO）慢性自发性 UC 中，结肠组织中促血管生成生长因子 VEGF 和其受体 VEGFR-2 的表达增加。大鼠急性 6%碘乙酰胺诱导的 UC 的发展伴随着 Erk1/2 和 Src 激酶的激活，而 Erk1/2 和 Src 的总蛋白表达不变。在慢性结肠炎中，与野生型小鼠相比，IL-10 KO 小鼠的 Erk1/2 磷酸化（即激活）显著降低。总 Erk1/2 蛋白水平不变，但 IL-10 KO 小鼠的总 Src 蛋白及其磷酸化形式的表达显著增加。总 Akt 蛋白没有变化，而激活的 Akt（pAkt）水平在 IL-10 KO 小鼠中略有增加。我们得出结论，介导血管通透性增加的 VEGF/VEGFR-2 相关信号转导途径（Src、Akt）可能在慢性实验性 UC 的持续存在中发挥核心作用。
