An important role of matrix metalloproteinase-8 in angiogenesis in vitro and in vivo
An important role of matrix metalloproteinase-8 in angiogenesis in vitro and in vivo
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DOI：
10.1093/cvr/cvt060
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发表时间：
2013-07-01
影响因子：
10.8
通讯作者：
Xiao, Qingzhong
中科院分区：
文献类型：
--
作者：
Fang, Changcun;Wen, Guanmei;Xiao, Qingzhong
越来越多的证据表明斑块血管生成与动脉粥样硬化斑块的形成和进展密切相关，基质金属蛋白酶（MMP）在血管生成和动脉粥样硬化中起重要作用。我们试图研究MMP8在血管生成中的功能参与。用MMP-8 shRNA慢病毒敲低人脐静脉内皮细胞（HuVECs）的MMP8，导致体外毛细血管样网络形成、细胞增殖和迁移减少，并损害其体内血管生成能力。在内源性MMP8表达水平较低的HuVECs中，-catenin的核积累较少，-catenin靶基因表达水平较低。HuVECs中内源性MMP8的敲低通过将较少的血管紧张素I转化为II来下调血小板/内皮细胞粘附分子-1 （PECAM-1）的表达，而血管紧张素I是PECAM-1基因表达的诱诱剂。从MMP8(/)/apoE（/）小鼠分离的主动脉环内皮细胞发芽较少，MMP8(/)/apoE（/）小鼠的内皮细胞向Matrigel塞的迁移能力较低，增殖和血管生成能力较差。此外，免疫组织化学分析显示，MMP8在人动脉粥样硬化斑块和动脉瘤的微血管中表达。最后，对Western diet喂养12周的MMP8(/)/apoE（/）和MMP8(/)/apoE（/）小鼠的分析表明，MMP8缺陷小鼠的病变面积较小，动脉粥样硬化病变内内皮细胞较少。我们首次证明了MMP8在体外和体内血管生成中发挥重要作用。我们的研究结果为斑块血管生成的分子机制提供了新的见解，并表明MMP8是心血管疾病的潜在治疗靶点。
Growing evidence suggests a close association of plaque angiogenesis with atherosclerotic plaque formation and progression, and an important role of matrix metalloproteinase (MMP) in angiogenesis and atherosclerosis. We attempted to investigate the functional involvements of MMP8 in angiogenesis.Knockdown of MMP8 in human umbilical vein endothelial cells (HuVECs) with MMP-8 shRNA lentivirus resulted in a decrease in in vitro capillary-like network formation, cell proliferation and migration, and impaired its capacity of in vivo angiogenesis. Less nuclear accumulation of -catenin and lower -catenin target gene expression levels was observed in the HuVECs expressing lower levels of endogenous MMP8. Knockdown of endogenous MMP8 in HuVECs down-regulated platelet/endothelial cell adhesion molecule-1 (PECAM-1) expression by converting less angiotensin I to II, which is an inducer for PECAM-1 gene expression. Aortic rings isolated from MMP8(/)/apoE(/) mice had less endothelial cell sprouting, and endothelial cells in MMP8(/)/apoE(/) mice had a lower ability to migrate into Matrigel plugs and less capacity of proliferation and angiogenesis. Moreover, immunohistochemical analyses revealed that MMP8 was expressed in microvessels within human atherosclerotic plaques and aneurysm. Finally, analyses of MMP8(/)/apoE(/) and MMP8(/)/apoE(/) mice fed a Western diet for 12 weeks showed that MMP8-deficient mice had small lesion size and less endothelial cells within atherosclerotic lesions.We demonstrated for the first time that MMP8 plays an important role in angiogenesis in vitro and in vivo. Our findings provide new insights into the molecular mechanisms of plaque angiogenesis and suggest that MMP8 is a potential therapeutic target of cardiovascular diseases.