Angiopoietins bind thrombomodulin and inhibit its function as a thrombin cofactor.
Angiopoietins bind thrombomodulin and inhibit its function as a thrombin cofactor.
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DOI：
10.1038/s41598-017-18912-8
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发表时间：
2018-01-11
影响因子：
4.6
通讯作者：
Davis S
中科院分区：
文献类型：
--
作者：
Daly C;Qian X;Castanaro C;Pasnikowski E;Jiang X;Thomson BR;Quaggin SE;Papadopoulos N;Wei Y;Rudge JS;Thurston G;Yancopoulos GD;Davis S
血管生成素-1 （Ang1）和血管生成素-2 （Ang2）是Tie2的配体，Tie2是一种内皮特异性受体酪氨酸激酶，是血管生成的重要调节剂。在这里，我们报告了通过表达克隆鉴定血栓调节蛋白（TM）作为Ang1和Ang2的另一个受体。凝血调节蛋白是一种内皮细胞表面分子，在凝血酶介导的抗凝蛋白蛋白C的活化以及凝血酶活化纤维蛋白溶解抑制剂（TAFI）中作为辅助因子发挥着凝血抑制剂的重要作用。Ang1和Ang2抑制体外培养内皮细胞凝血酶/TM介导的活化蛋白C和TAFI的生成，抑制凝血酶与TM的结合。与Ang1相比，Ang2似乎与TM具有更高的亲和力，是一种更有效的TM功能抑制剂。与血管生成素在凝血中的潜在作用一致，给小鼠使用凝血酶可迅速增加血浆Ang1水平，可能反映了活化血小板（先前显示含有高水平的Ang1）的释放。此外，伤口血液制备的血浆中Ang1水平显著升高，表明Ang1从血管损伤部位的活化血小板中释放。我们的结果暗示了先前描述的血管生成素在止血调节中的作用。
Angiopoietin-1 (Ang1) and Angiopoietin-2 (Ang2) are ligands for Tie2, an endothelial-specific receptor tyrosine kinase that is an essential regulator of angiogenesis. Here we report the identification, via expression cloning, of thrombomodulin (TM) as another receptor for Ang1 and Ang2. Thrombomodulin is an endothelial cell surface molecule that plays an essential role as a coagulation inhibitor via its function as a cofactor in the thrombin-mediated activation of protein C, an anticoagulant protein, as well as thrombin-activatable fibrinolysis inhibitor (TAFI). Ang1 and Ang2 inhibited the thrombin/TM-mediated generation of activated protein C and TAFI in cultured endothelial cells, and inhibited the binding of thrombin to TM in vitro. Ang2 appears to bind TM with higher affinity than Ang1 and is a more potent inhibitor of TM function. Consistent with a potential role for angiopoietins in coagulation, administration of thrombin to mice rapidly increased plasma Ang1 levels, presumably reflecting release from activated platelets (previously shown to contain high levels of Ang1). In addition, Ang1 levels were significantly elevated in plasma prepared from wound blood, suggesting that Ang1 is released from activated platelets at sites of vessel injury. Our results imply a previously undescribed role for angiopoietins in the regulation of hemostasis.
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影响因子：
8.8
作者：
David S;Mukherjee A;Ghosh CC;Yano M;Khankin EV;Wenger JB;Karumanchi SA;Shapiro NI;Parikh SM
通讯作者：
Parikh SM
影响因子：
11.8
作者：
Gale, NW;Thurston, G;Yancopoulos, GD
通讯作者：
Yancopoulos, GD
DOI：
10.1038/nsb880
发表时间：
2003-01-01
期刊：
NATURE STRUCTURAL BIOLOGY
影响因子：
--
作者：
Davis, S;Papadopoulos, N;Yancopoulos, GD
通讯作者：
Yancopoulos, GD
影响因子：
4.8
作者：
Carlson, TR;Feng, YZ;Morla, AO
通讯作者：
Morla, AO
影响因子：
11.2
作者：
Daly, Christopher;Eichten, Alexandra;Thurston, Gavin
通讯作者：
Thurston, Gavin