Inhibition of endothelial cell migration, intercellular communication, and vascular tube formation by thromboxane A2
Inhibition of endothelial cell migration, intercellular communication, and vascular tube formation by thromboxane A2
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DOI：
10.1074/jbc.274.50.35562
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发表时间：
1999-12-10
影响因子：
4.8
通讯作者：
Ware, JA
中科院分区：
文献类型：
--
作者：
Ashton, AW;Yokota, R;Ware, JA
二十烷类血栓烷A(2)(TXA(2))由活化的血小板、单核细胞和血管壁释放，并与包括内皮在内的多种组织中表达的高亲和力受体相互作用。目前尚不清楚TXA(2)是否会改变血管生成的两个决定因素--内皮细胞迁移和血管形成。因此，我们研究了血栓素A(2)类似物[1S-(1α，2β(5Z)，3α(1E，3R)，4 alpha]-7-[3-(3-hydroxy-4-(4‘-iodophenoxy)-1-butenyl)-7-oxabicyclo-[2.2.1]heptan-2-yl]-5’-heptenoic酸(IBOP)]对体外培养的人内皮细胞迁移和血管生成的影响。IBOP刺激可抑制REC迁移50%，抑制体外毛细血管形成75%。IBOP的这些作用是时间和浓度依赖的，IC50为25 nM。IBOP不影响HEC整合素的表达和细胞骨架的形态。由于缝隙连接介导的细胞间通讯在迁移的HEC中增加，我们确定IBOP是否可能抑制HEC的偶联或连接蛋白的表达。IBOP将微注射染料在HEC之间的传递减少了50%，IBOP对迁移和管状形成的影响可被缝隙连接抑制剂18β-甘草次酸(1MU M)模拟，具有类似的时间进程和效果。IBOP(24 H)不影响整个HEC裂解物中连接蛋白43的表达或磷酸化。HEC的免疫组织化学检查表明，IBOP可能通过改变缝隙连接的细胞分布，导致连接蛋白43内化增加，从而损害功能偶联。因此，这一发现表明，TXA(2)类似物可能通过损害细胞间通讯来阻止HEC的迁移和管子的形成，这表明拮抗TXA(2)信号可能增强缺血组织的血管形成。
The eicosanoid thromboxane A(2) (TXA(2)) is released by activated platelets, monocytes, and the vessel wall and interacts with high affinity receptors expressed in several tissues including endothelium. Whether TXA(2) might alter endothelial migration and tube formation, two determinants of angiogenesis, is unknown. Thus, we investigated the effect of the TXA(2) mimetic [1S-(1 alpha,2 beta(5Z)),3 alpha(1E,3R),4 alpha]-7-[3-(3-hydroxy-4-(4'-iodophenoxy)-1-butenyl)-7-oxabicyclo-[2.2.1]heptan-2-yl]-5'-heptenoic acid (IBOP) on human endothelial cell (HEC) migration and angiogenesis in vitro. IBOP stimulation inhibited REC migration by 50% and in vitro capillary formation by 75%. These effects of IBOP were time- and concentration-dependent with an IC50 of 25 nM. IBOP did not affect integrin expression or cytoskeletal morphology of HEC. Since gap junction-mediated intercellular communication increases in migrating HEC, we determined whether IBOP might inhibit coupling or connexin expression in HEC. IBOP reduced the passage of microinjected dyes between HEC by 50%, and the effects of IBOP on migration and tube formation were mimicked by the gap junction inhibitor 18 beta-glycyrrhetinic acid (1 mu M) with a similar time course and efficacy. IBOP (24 h) did not affect the expression or phosphorylation of connexin 43 in whole HEC lysates. Immunohistologic examination of HEC suggested that IBOP may impair functional coupling by altering the cellular distribution of gap junctions, leading to increased connexin 43 internalization. Thus, this finding that TXA(2) mimetics can prevent HEC migration and tube formation, possibly by impairing intercellular communication, suggests that antagonizing TXA(2) signaling might enhance vascularization of ischemic tissue.