The non-proteolytically active thrombin peptide TP508 stimulates angiogenic sprouting.
The non-proteolytically active thrombin peptide TP508 stimulates angiogenic sprouting.
复制标题
非蛋白水解活性凝血酶肽 TP508 刺激血管生成萌芽。
DOI：
10.1002/jcp.20442
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发表时间：
2006
影响因子：
5.6
通讯作者：
Hoying,JamesB
中科院分区：
文献类型：
--
作者：
Vartanian,KeriB;Chen,HelenYS;Kennedy,Janelle;Beck,ShaleenK;Ryaby,JamesT;Wang,Hali;Hoying,JamesB
凝血酶是一种丝氨酸蛋白酶，可促进血小板聚集、血液凝固和组织修复。源自凝血酶非蛋白水解活性区域的肽 TP508 也能促进组织修复和增加血管分布，但不会激活血小板和炎症级联反应。 TP508 以高亲和力与细胞结合，并刺激独立于蛋白水解活性凝血酶受体 (PAR) 的细胞，因此被认为可以激活非蛋白水解活性受体 (non-PAR) 途径。使用血管生成萌芽模型，我们进一步确定了 TP508 的血管生成潜力，并研究了非蛋白水解、凝血酶介导的途径在血管生成中的作用。该测定涉及测量培养的完整微血管碎片的血管生成萌芽。在此测定中，TP508 刺激血管生成萌芽的程度类似于或大于强效血管生成因子 VEGF。然而，TP508 对每个容器形成的芽的数量没有显着影响。与 TP508 相比，蛋白水解活性受体激动剂没有作用或抑制血管生成萌芽。 TP508 刺激的发芽活性增加是 VEGF 依赖性的，但不涉及 VEGF mRNA 表达增加至基线水平以上。这些结果表明，TP508 在血管生成早期直接作用于微血管细胞以加速出芽，但不会诱导更多出芽，其方式与完整的凝血酶分子不同。 © 2005 Wiley-Liss, Inc.
Thrombin is a serine protease that promotes platelet aggregation, blood coagulation, and tissue repair. A peptide derived from a non‐proteolytically active region of thrombin, TP508, also promotes tissue repair and increased vascularity, yet does not activate platelet and inflammatory cascades. TP508 binds to cells with high affinity and stimulates cells independent of the proteolytically active thrombin receptors (PARs) and thus is considered to activate a non‐proteolytically active receptor (non‐PAR) pathway. Using a model of angiogenic sprouting, we further defined the angiogenic potential of TP508 and investigated the role of non‐proteolytic, thrombin‐mediated pathways in angiogenesis. The assay involves measuring angiogenic sprouting from cultured, intact microvessel fragments. In this assay, TP508 stimulated angiogenic sprouting to an extent similar to or greater than the potent angiogenic factor, VEGF. However, TP508 had no significant effect on the number of sprouts that formed per vessel. In contrast to TP508, proteolytically active receptor agonists had no effect or inhibited angiogenic sprouting. The increased sprouting activity stimulated by TP508 was VEGF dependent but did not involve an increase in VEGF mRNA expression above baseline levels. These results suggest that TP508 acts early in angiogenesis and directly on microvascular cells to accelerate sprouting, but not to induce more sprouting, in a manner different than the intact thrombin molecule. © 2005 Wiley‐Liss, Inc.