Serine Protease Activation Essential for Endothelial-Mesenchymal Transition in Vascular Calcification.
Serine Protease Activation Essential for Endothelial-Mesenchymal Transition in Vascular Calcification.
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DOI：
10.1161/circresaha.115.306751
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发表时间：
2015-10-09
影响因子：
20.1
通讯作者：
Yao Y
中科院分区：
文献类型：
--
作者：
Yao J;Guihard PJ;Blazquez-Medela AM;Guo Y;Moon JH;Jumabay M;Boström KI;Yao Y
内皮细胞具有经历内皮-间充质转化（EndMT）的能力，通过所述内皮-间充质转化，它们获得间充质表型和干细胞样特征。我们以前发现EndMT发生在基质Gla蛋白（MGP）缺乏的内皮细胞中，使内皮细胞能够为血管钙化提供细胞。然而，负责启动终端MT的机制尚未完全了解。确定特异性丝氨酸蛋白酶和性别决定区Y-box 2（Sox 2）在EndMT起始中的作用。在这项研究中，我们使用体内和体外模型的血管钙化，以证明丝氨酸蛋白酶和Sox 2是必不可少的MGP缺陷的内皮细胞中的EndMT的启动。我们发现，一组特定的丝氨酸蛋白酶的表达是高度诱导的血管钙化部位的血管内皮细胞中的Mgp空血管瘤。丝氨酸蛋白酶抑制剂治疗降低了干细胞标志物表达和血管钙化。在人主动脉内皮细胞中，这组丝氨酸蛋白酶也诱导EndMT，并且蛋白酶的激活由Sox 2介导。丝氨酸蛋白酶或Sox 2的敲低减少了EndMT和钙化。内皮特异性Sox 2缺失降低MGP缺陷小鼠干细胞标志物表达和主动脉钙化我们的研究结果表明，Sox 2介导的特定丝氨酸蛋白酶的激活是启动EndMT所必需的，因此，可能为治疗血管钙化提供新的治疗靶点。
Endothelial cells have the ability to undergo endothelial-mesenchymal transitions (EndMTs), by which they acquire a mesenchymal phenotype and stem-cell like characteristics. We previously found that EndMTs ocurred in the endothelium deficient in matrix Gla protein (MGP) enabling endothelial cells to contribute cells to vascular calcification. However, the mechanism responsible for initiating EndMTs is not fully understood. To determine the role of specific serine proteases and sex determining region Y-box 2 (Sox2) in the initiation of EndMTs. In this study, we used in vivo and in vitro models of vascular calcification to demonstrate that serine proteases and Sox2 are essential for the initiation of EndMTs in MGP-deficient endothelium. We showed that expression of a group of specific serine proteases was highly induced in endothelial cells at sites of vascular calcification in Mgp null aortas. Treatment with serine protease inhibitors decreased both stem-cell marker expression and vascular calcification. In human aortic endothelial cells, this group of serine proteases also induced EndMTs, and the activation of proteases was mediated by Sox2. Knockdown of the serine proteases or Sox2 diminished EndMTs and calcification. Endothelial-specific deletion of Sox2 decreased expression of stem-cell markers and aortic calcification in MGP-deficient mice. Our results suggest that Sox2-mediated activation of specific serine proteases is essential for initiating EndMTs, and thus, may provide new therapeutic targets for treating vascular calcification.