An Autocrine Linkage Between Matrix Metalloproteinase-14 and Tie-2 Via Ectodomain Shedding Modulates Angiopoietin-1-Dependent Function in Endothelial Cells
An Autocrine Linkage Between Matrix Metalloproteinase-14 and Tie-2 Via Ectodomain Shedding Modulates Angiopoietin-1-Dependent Function in Endothelial Cells
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DOI：
10.1161/atvbaha.109.201111
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发表时间：
2010-04-01
影响因子：
8.7
通讯作者：
Sueishi, Katsuo
中科院分区：
文献类型：
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作者：
Onimaru, Mitsuho;Yonemitsu, Yoshikazu;Sueishi, Katsuo
血管生成素（Angiopoietin，Ang）-Tie-2系统在胎儿和成人血管生成过程中起关键作用。在此，我们探讨了Tie-2脱落相关的分子机制和病理生理学significant.Methods和Results-By使用小鼠后肢缺血模型，我们观察到分离的表达全长Tie-2（fTie-2）蛋白和Tie-2 mRNA在大腿肌肉缺血手术后1天，这表明，fTie-2的表达是通过在体内的转录后调控修改。通过用siRNA-基质金属蛋白酶（MMP）14或金属蛋白酶3的组织抑制剂处理显著抑制人脐静脉内皮细胞中产生的可溶形式的Tie-2，导致细胞fTie-2增加，从而增强Ang-1依赖性Akt磷酸化和Akt依赖性内皮功能，例如Ang-2下调或内皮活力增加。佛波醇-12-肉豆蔻酸酯-13乙酸酯（PMA）通过蛋白激酶C-细胞外信号调节激酶途径上调MMP-14 mRNA，并以MMP-14依赖的方式增强可溶性Tie-2的产生，导致细胞fTie-2的减少。此外，PMA诱导的可溶性Tie-2是通过蛋白激酶C-细胞外信号调节激酶信号通路介导的。最后，下调的金属蛋白酶3和MMP-14 mRNA的上调组织抑制剂被证实在缺血大腿muscle 1天后operation. Conclusion-A自分泌连接之间的内皮蛋白激酶C-MMP-14轴和Tie-2脱落被证明是一种新的调节机制，为Ang-Tie-2系统，并可能发挥作用，在血管生成过程中调节内皮功能。（Arterioscler Thromb Vasc Biol.2010; 30：818-826.）
Objective-The angiopoietin (Ang)-Tie-2 system plays a critical role during fetal and adult angiogenesis. Herein, we explored the Tie-2 shedding-related molecular mechanisms and the pathophysiological significance.Methods and Results-By using a mouse hindlimb ischemia model, we observed dissociated expression between the full-length Tie-2 (fTie-2) protein and Tie-2 mRNA in thigh muscles 1 day after an ischemic operation, suggesting that fTie-2 expression was modified through the posttranscriptional regulation in vivo. A soluble form of Tie-2 produced in human umbilical vein endothelial cells was dramatically suppressed by treatment with siRNA-matrix metalloproteinase (MMP) 14 or tissue inhibitor of metalloproteinase 3, resulting in an increase in cellular fTie-2 and thereby enhancing Ang-1-dependent Akt phosphorylation and Akt-dependent endothelial functions, such as Ang-2 downregulation or an increase of endothelial viability. Phorbol-12-myristate-13 acetate (PMA) upregulates MMP-14 mRNA via protein kinase C-extracellular signal-regulated kinase pathways, and enhanced soluble Tie-2 production in an MMP-14-dependent manner, resulting in a reduction of cellular fTie-2. In addition, the PMA-induced soluble Tie-2 was mediated by the protein kinase C-extracellular signal-regulated kinase signaling pathways. Finally, downregulation of tissue inhibitor of metalloproteinase 3 and upregulation of MMP-14 mRNA were confirmed in ischemic thigh muscles 1 day after the operation.Conclusion-An autocrine linkage between the endothelial protein kinase C-MMP-14 axis and Tie-2 shedding was shown to be a novel regulatory mechanism for the Ang-Tie-2 system and may play a role in modulating endothelial function during angiogenesis. (Arterioscler Thromb Vasc Biol. 2010; 30: 818-826.)