Division of Pathophysiological and Experimental Pathology, Department of Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Arterioscler Thromb Vasc Biol. 2010 Apr;30(4):818-26. doi: 10.1161/ATVBAHA.109.201111. Epub 2010 Jan 7.
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.
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.
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.
血管生成素（Ang）-Tie-2 系统在胎儿和成人血管生成中起着关键作用。在此，我们探讨了 Tie-2 脱落相关的分子机制及其病理生理意义。
通过使用小鼠后肢缺血模型，我们在缺血手术后 1 天观察到大腿肌肉中全长 Tie-2（fTie-2）蛋白与 Tie-2mRNA 的分离表达，这表明 fTie-2 的表达通过体内的转录后调节进行修饰。在人脐静脉内皮细胞中产生的可溶性 Tie-2 形式通过 siRNA-基质金属蛋白酶（MMP）14 或组织抑制剂的处理被显著抑制金属蛋白酶 3，导致细胞内 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，如 Ang-2 下调或内皮活力增加。佛波醇 12-肉豆蔻酸 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-14mRNA，并以 MMP-14 依赖的方式增强可溶性 Tie-2 的产生，导致细胞内 fTie-2 的减少。此外，PMA 诱导的可溶性 Tie-2是由蛋白激酶 C-细胞外信号调节激酶信号通路介导的。最后，在手术后 1 天，缺血大腿肌肉中证实了组织抑制剂的下调 MMP-14mRNA 和上调。
内皮蛋白激酶 C-MMP-14 轴与 Tie-2 脱落之间的自分泌联系被证明是 Ang-Tie-2 系统的一种新的调节机制，可能在调节血管生成期间内皮功能中发挥作用。
