Modulation of endothelial cell migration by extracellular nucleotides - Involvement of focal adhesion kinase and phosphatidylinositol 3-kinase-mediated pathways
Modulation of endothelial cell migration by extracellular nucleotides - Involvement of focal adhesion kinase and phosphatidylinositol 3-kinase-mediated pathways
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DOI：
10.1160/th04-09-0576
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发表时间：
2005-04-01
影响因子：
6.7
通讯作者：
Robson, SC
中科院分区：
文献类型：
--
作者：
Kaczmarek, E;Erb, L;Robson, SC
细胞外核苷酸与2型嘌呤能/嘧啶能（P2）受体结合，所述2型嘌呤能/嘧啶能（P2）受体介导各种反应，如细胞活化、增殖和凋亡，涉及炎症过程。P2受体及其相关信号转导通路在内皮细胞反应中的作用尚未得到充分研究。在这里，它表明，刺激人脐静脉内皮细胞（HUVEC）与细胞外ATP或UTP增加细胞内游离钙离子浓度（[Ca 2 +]（i）），诱导磷酸化的粘着斑激酶（FAK），p130（cas）和桩蛋白，并导致细胞骨架重排，随之而来的细胞迁移。此外，UTP以磷脂酰肌醇3-激酶（P13-K）依赖的方式增加HUVEC的迁移。BAPTA或毒胡萝卜素抑制细胞外核苷酸诱导的[Ca 2 +]（i）增加，这是FAK磷酸化和细胞迁移的关键反应。此外，HUVEC长期暴露于G蛋白偶联的P2 Y2和P2 Y 4受体亚型的ATP和UTR激动剂，导致α（v）整联蛋白表达上调，α（v）整联蛋白是已知与P2 Y2受体直接相互作用的细胞粘附分子。我们的研究结果表明，细胞外核苷酸调节信号通路在HUVEC影响细胞功能，如细胞骨架的变化，细胞粘附和运动，通常与整合素激活和生长因子的作用。我们认为P2 Y2和可能的P2 Y 4受体介导了在血管炎症、动脉粥样硬化和血管生成中重要的那些反应。
Extracellular nucleoticles bind to type-2 purinergic/pyrimidinergic (P2) receptors that mediate various responses, such as cell activation, proliferation and apoptosis, implicated in inflammatory processes. The role of P2 receptors and their associated signal transduction pathways in endothelial cell responses has not been fully investigated. Here, it is shown that stimulation of human umbilical vein endothelial cells (HUVEC) with extracellular ATP or UTP increased intracellular free calcium ion concentrations ([Ca2+](i)), induced phosphorylation of focal adhesion kinase (FAK), p130(cas) and paxillin, and caused cytoskeletal rearrangements with consequent cell migration. Furthermore, UTP increased migration of HUVEC in a phosphaticlylinositol 3-kinase (P13-K)-dependent manner. BAPTA or thapsigargin in-hibited the extracellular nucleotide-incluced increase in [Ca2+](i), a response crucial for both FAK phosphorylation and cell migration. Furthermore, long-term exposure of HUVEC to ATP and UTR agonists of the G protein-coupled P2Y2 and P2Y4 receptor subtypes, caused upregulation of alpha(v) integrin expression, a cell adhesion molecule known to directly interact with P2Y2 receptors. Our results suggest that extracellular nucleotides modulate signaling pathways in HUVEC influencing cell functions, such as cytoskeletal changes, cellular adhesion and motility, typically associated with integrin-activation and the action of growth factors. We propose that P2Y2 and possibly P2Y4 receptors mediate those responses that are important in vascular inflammation, atherosclerosis and angiogenesis.