Aminopeptidase A is a functional target in angiogenic blood vessels
Aminopeptidase A is a functional target in angiogenic blood vessels
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DOI：
10.1016/s1535-6108(04)00025-x
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发表时间：
2004-02-01
期刊：
影响因子：
50.3
通讯作者：
Arap, W
中科院分区：
文献类型：
--
作者：
Marchiò, S;Lahdenranta, J;Arap, W
我们发现，膜相关蛋白酶，氨肽酶A（阿帕），是上调和酶活性在血管中的人类肿瘤。为了获得机制的见解，我们评估了阿帕基因敲除小鼠的血管生成。我们发现，尽管这些小鼠发育正常，但它们未能对缺氧或生长因子产生预期的血管生成反应。然后，我们从肽库中分离出阿帕的肽抑制剂，并表明它们特异性地结合并抑制阿帕，抑制内皮细胞的迁移和增殖，抑制血管生成，并归巢肿瘤血管。最后，我们成功地用阿帕结合肽或抗APA阻断单克隆抗体治疗荷瘤小鼠。这些数据表明阿帕是血管形成的调节剂，并且可以作为功能性血管靶点。
We show that a membrane-associated protease, aminopeptidase A (APA), is upregulated and enzymatically active in blood vessels of human tumors. To gain mechanistic insight, we evaluated angiogenesis in APA null mice. We found that, although these mice develop normally, they fail to mount the expected angiogenic response to hypoxia or growth factors. We then isolated peptide inhibitors of APA from a peptide library and show that they specifically bind to and inhibit APA, suppress migration and proliferation of endothelial cells, inhibit angiogenesis, and home to tumor blood vessels. Finally, we successfully treated tumor-bearing mice with APA binding peptides or anti-APA blocking monoclonal antibodies. These data show that APA is a regulator of blood vessel formation, and can serve as a functional vascular target.