Glycogen-synthase kinase3β/β-catenin axis promotes angiogenesis through activation of vascular endothelial growth factor signaling in endothelial cells
Glycogen-synthase kinase3β/β-catenin axis promotes angiogenesis through activation of vascular endothelial growth factor signaling in endothelial cells
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DOI：
10.1161/01.res.0000156273.30274.f7
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发表时间：
2005-02-18
影响因子：
20.1
通讯作者：
Walsh, K
中科院分区：
文献类型：
--
作者：
Skurk, C;Maatz, H;Walsh, K
糖原合成酶激酶3 β（Glycogen-Synthase Kinase 3 beta，GSK 3 beta）是内皮细胞信号通路的节点，调节血管生长，但GSK 3 β下游的信号机制尚未明确。在这里，我们表明，β-连环蛋白是一个重要的下游目标GSK 3 β作用在血管生成和解剖的信号转导途径参与血管生成表型。用激酶突变形式的酶（KM-GSK 3 β）转导人脐静脉内皮细胞（HUVEC）可增加细胞溶质β-连环蛋白水平，而组成型活性GSK 3 β（S9 A-GSK 3 β）可降低β-连环蛋白水平。KM-GSK 3 β可上调类磷脂增强因子/T细胞因子启动子活性，S9 A-GSK 3 β可降低其活性，而Akt信号的调控对该参数无影响。β-连环蛋白转导在体内基质胶栓塞测定中诱导毛细血管形成，并在体外基质胶包被的板上促进内皮细胞分化成网络结构。β-连环蛋白激活血管内皮生长因子（VEGF）-A和VEGF-C在内皮细胞中的表达，并且这些作用在蛋白质、mRNA和启动子活性水平上介导。与这些数据一致，β-连环蛋白增加VEGF受体2（VEGF-R2）的磷酸化并促进其与PI 3-激酶的结合，导致丝氨酸-苏氨酸激酶Akt的剂量依赖性活化。PI 3激酶或Akt信号的抑制导致β-连环蛋白的促血管生成活性显著降低。总的来说，这些数据表明，生长因子-PI 3-激酶-Akt轴在内皮细胞中的GSK 3 β/β-连环蛋白信号传导下游起作用以促进血管生成。
Glycogen-Synthase Kinase 3beta (GSK3beta) has been shown to function as a nodal point of converging signaling pathways in endothelial cells to regulate vessel growth, but the signaling mechanisms downstream from GSK3beta have not been identified. Here, we show that beta-catenin is an important downstream target for GSK3beta action in angiogenesis and dissect the signal transduction pathways involved in the angiogenic phenotype. Transduction of human umbilical vein endothelial cells (HUVECs) with a kinase-mutant form of the enzyme (KM-GSK3beta) increased cytosolic beta-catenin levels, whereas constitutively active GSK3beta (S9A-GSK3beta) reduced beta-catenin levels. Lymphoid enhancer factor/T-cell factor promoter activity was upregulated by KM-GSK3beta and diminished by S9A-GSK3beta, whereas manipulation of Akt signaling had no effect on this parameter. beta-Catenin transduction induced capillary formation in a Matrigel-plug assay in vivo and promoted endothelial cell differentiation into network structures on Matrigel-coated plates in vitro. beta-Catenin activated the expression of vascular endothelial growth factor (VEGF)-A and VEGF-C in endothelial cells, and these effects were mediated at the levels of protein, mRNA, and promoter activity. Consistent with these data, beta-catenin increased the phosphorylation of the VEGF receptor 2 (VEGF-R2) and promoted its association with PI3-kinase, leading to a dose-dependent activation of the serine-threonine kinase Akt. Inhibition of PI3-kinase or Akt signaling led to a significant reduction in the pro-angiogenic activity of beta-catenin. Collectively, these data show that the growth factor-PI3-kinase-Akt axis functions downstream of GSK3beta/beta-catenin signaling in endothelial cells to promote angiogenesis.