Hepatocyte growth factor enhances endothelial cell barrier function and cortical cytoskeletal rearrangement:: potential role of glycogen synthase kinase-3β
Hepatocyte growth factor enhances endothelial cell barrier function and cortical cytoskeletal rearrangement:: potential role of glycogen synthase kinase-3β
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DOI：
10.1096/fj.01-0870com
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发表时间：
2002-07-01
期刊：
影响因子：
4.8
通讯作者：
Garcia, JGN
中科院分区：
文献类型：
--
作者：
Liu, F;Schaphorst, KL;Garcia, JGN
新形成的毛细血管内内皮细胞（EC）屏障功能的稳定是血管生成的关键特征。我们研究了肝细胞生长因子（HGF），一种公认的血管生成因子和EC化学引诱物引起的人肺EC屏障调节。HGF快速且剂量依赖性地升高EC单层的跨内皮电阻（TER）（100 ng/ml时增加>50%），免疫荧光显微镜证据表明细胞质肌动蛋白应力纤维溶解和皮质肌动蛋白环的强烈增强。HGF快速刺激磷脂酰肌醇3 '-激酶、ERK、p38丝裂原活化蛋白激酶和蛋白激酶C的活性。药理学抑制剂研究表明，每种途径都与HGF诱导的TER增加、皮质肌动蛋白增厚和Ser/Thr糖原合成酶激酶-3 β（GSK-3 β）磷酸化密切相关，GSK-3 β是HGF屏障促进反应的潜在靶标。GSK-3 β磷酸化与HGF诱导的TER减少和在细胞-细胞连接处观察到的增强的β-连环蛋白免疫反应性密切相关。我们的数据表明，在一个模型中，HGF介导的EC细胞骨架重排和屏障增强严重依赖于一个复杂的激酶级联的激活，收敛在GSK-3 β，以增加β-连环蛋白的可用性，从而增强内皮连接的完整性和血管屏障功能。
The stabilization of endothelial cell (EC) barrier function within newly formed capillaries is a critical feature of angiogenesis. We examined human lung EC barrier regulation elicited by hepatocyte growth factor (HGF), a recognized angiogenic factor and EC chemoattractant. HGF rapidly and dose-dependently elevated transendothelial electrical resistance (TER) of EC monolayers (>50% increase at 100 ng/ml), with immunofluorescence microscopic evidence of both cytoplasmic actin stress fiber dissolution and strong augmentation of the cortical actin ring. HGF rapidly stimulated phosphatidylinositol 3'-kinase, ERK, p38 mitogen-activated protein kinase, and protein kinase C activities. Pharmacological inhibitor studies demonstrated each pathway to be intimately involved in HGF-induced increases in TER, cortical actin thickening, and phosphorylation of the Ser/Thr glycogen synthase kinase-3beta (GSK-3beta), a potential target for the HGF barrier-promoting response. GSK-3beta phosphorylation was strongly correlated with reductions in both HGF-induced TER and enhanced beta-catenin immunoreactivity observed at cell-cell junctions. Our data suggest a model in which HGF-mediated EC cytoskeletal rearrangement and barrier enhancement depend critically on the activation of a complex kinase cascade that converges at GSK-3beta to increase the availability of beta-catenin, thereby enhancing endothelial junctional integrity and vascular barrier function.