Vascular endothelial growth factor expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin through nuclear factor-κB activation in endothelial cells
Vascular endothelial growth factor expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin through nuclear factor-κB activation in endothelial cells
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DOI：
10.1074/jbc.m009705200
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发表时间：
2001-03-09
影响因子：
4.8
通讯作者：
Koh, GY
中科院分区：
文献类型：
--
作者：
Kim, I;Moon, SO;Koh, GY
血管内皮生长因子（VEGF）在炎症过程中诱导内皮细胞上的粘附分子。在这里，我们研究了VEGF刺激人脐静脉内皮细胞表达细胞间粘附分子1（ICAM-1），血管细胞粘附分子1（VCAM-1）1和E-选择素的机制。VEGF（20 ng/ml）以时间依赖性方式增加ICAM-1、VCAM-1和E-选择素mRNA的表达。这些作用被Flk-1/含激酶插入结构域的受体（KDR）拮抗剂和磷脂酶C、核因子（NF）-B-K、鞘氨醇激酶和蛋白激酶C的抑制剂显著抑制，但它们不受促分裂原活化蛋白/细胞外信号调节激酶激酶（MEK）1/2或一氧化氮合酶抑制剂的影响。磷脂酰肌醇（PI）3 ′-激酶抑制剂wortmannin增强了基础和VEGF刺激的粘附分子表达，而PI 3 ′-激酶激活剂胰岛素抑制了基础和VEGF刺激的粘附分子表达。凝胶位移分析显示VEGF刺激NF-B-K活性，这种作用被磷脂酶C抑制，NF-κ B或蛋白激酶C抑制剂VEGF以NF-κ B依赖的方式增加VCAM-1和ICAM-1蛋白水平并增加白细胞增殖。这些结果表明，VEGF刺激ICAM-1，VCARI-1和E-选择素mRNA的表达主要是通过NF-κ B激活和PI 3 ′-激酶介导的抑制，但不依赖于一氧化氮和MEK，因此，VEGF同时激活两个信号转导通路，这两个通路在诱导粘附分子表达中具有相反的功能。平行反向信号的存在意味着VEGF对粘附分子表达的诱导受到非常精细的调节。
Vascular endothelial growth factor (VEGF) induces adhesion molecules on endothelial cells during inflammation. Here we examined the mechanisms underlying VEGF-stimulated expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1)1 and E-selectin in human umbilical vein endothelial cells. VEGF (20 ng/ml) increased expression of ICAM-1, VCAM-1, and E-selectin mRNAs in a time-dependent manner. These effects were significantly suppressed by Flk-1/kinase-insert domain containing receptor (KDR) antagonist and by inhibitors of phospholipase C, nuclear factor (NF)-B-K, sphingosine kinase, and protein kinase C, but they were not affected by inhibitors of mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) 1/2 or nitric-oxide synthase, Unexpectedly, the phosphatidylinositol (PI) 3'-kinase inhibitor wortmannin enhanced both basal and VEGF-stimulated adhesion molecule expression, whereas insulin, a PI 3'-kinase activator, suppressed both basal and VEGF-stimulated expression, Gel shift analysis revealed that VEGF stimulated NF-B-K activity, This effect was inhibited by phospholipase C, NF-B-K, or protein kinase C inhibitor, VEGF increased VCAM-1 and ICAM-1 protein levels and increased leukocyte adhesiveness in a NF-KB-dependent manner. These results suggest that VEGF-stimulated expression of ICAM-1, VCARI-1, and E-selectin mRNAs was mainly through NF-KB activation with PI 3'-kinase-mediated suppression, but was independent of nitric oxide and MEK, Thus, VEGF simultaneously activates two signal transduction pathways that have opposite functions in the induction of adhesion molecule expression. The existence of parallel inverse signaling implies that the induction of adhesion molecule expression by VEGF is very finely regulated.