Impaired angiogenesis in aminopeptidase N-null mice
Impaired angiogenesis in aminopeptidase N-null mice
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DOI：
10.1073/pnas.0611653104
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发表时间：
2007-03-13
影响因子：
11.1
通讯作者：
Pasqualini, Renata
中科院分区：
文献类型：
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作者：
Rangel, Roberto;Sun, Yan;Pasqualini, Renata
氨肽酶N（APN，CD 13; EC 3.4.11.2）是一种跨膜金属蛋白酶，具有多种功能，取决于细胞类型和组织环境。在肿瘤血管系统中，APN在内皮中过表达并促进血管生成。然而，目前还没有APN基因在体内失活的报告，以验证这些发现。在这里，我们评估，有针对性地破坏APN基因，APN是否参与血管形成和功能在正常条件下。令人惊讶的是，APN缺失小鼠没有出现肉眼或组织学异常。标准神经、心血管、代谢、运动和血液学研究显示无变化。尽管如此，在氧诱导的视网膜病变实验中，APN缺陷小鼠预期的视网膜新生血管明显缺乏，且呈剂量依赖性。此外，嵌入生长因子的明胶泡沫不能诱导APN-null小鼠的功能性血管形成。这些发现证实APN-无效小鼠正常发育而没有生理改变，并且可以经历生理血管生成，但在病理条件下显示严重受损的血管生成反应。最后，除了血管生物学研究之外，APN缺失小鼠可能是其他医学领域的有用试剂，例如恶性肿瘤，心血管，免疫学或感染性疾病。
Aminopeptidase N (APN, CD13; EC 3.4.11.2) is a transmembrane metalloprotease with several functions, depending on the cell type and tissue environment. In tumor vasculature, APN is overexpressed in the endothelium and promotes angiogenesis. However, there have been no reports of in vivo inactivation of the APN gene to validate these findings. Here we evaluated, by targeted disruption of the APN gene, whether APN participates in blood vessel formation and function under normal conditions. Surprisingly, APN-null mice developed with no gross or histological abnormalities. Standard neurological, cardiovascular, metabolic, locomotor, and hematological studies revealed no alterations. Nonetheless, in oxygen-induced retinopathy experiments, APN-deficient mice had a marked and dose-dependent deficiency of the expected retinal neovascularization. Moreover, gelfoams embedded with growth factors failed to induce functional blood vessel formation in APN-null mice. These findings establish that APN-null mice develop normally without physiological alterations and can undergo physiological angiogenesis but show a severely impaired angiogenic response under pathological conditions. Finally, in addition to vascular biology research, APN-null mice may be useful reagents in other medical fields such as malignant, cardiovascular, immunological, or infectious diseases.