Department of Cardiovascular Surgery, Qilu Hospital, School of Medicine, Shandong University, Jinan, China.
Cardiovasc Res. 2013 Jul 1;99(1):146-55. doi: 10.1093/cvr/cvt060. Epub 2013 Mar 19.
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 β-catenin and lower β-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.
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着重要作用。我们试图研究 MMP8 在血管生成中的功能作用。
用 MMP-8 shRNA 慢病毒转染人脐静脉内皮细胞（HuVEC），降低 MMP8 的表达，导致体外毛细血管样网络形成、细胞增殖和迁移减少，体内血管生成能力受损。在表达低水平内源性 MMP8 的 HuVEC 中，β-连环蛋白的核内积累减少，β-连环蛋白靶基因的表达水平降低。HuVEC 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/内皮细胞黏附分子-1（PECAM-1）的表达，血管紧张素 II 是 PECAM-1 基因表达的诱导剂。从 MMP8（-/-）/apoE（-/-）小鼠分离的主动脉环内皮细胞发芽较少，并且 MMP8（-/-）/apoE（-/-）小鼠的内皮细胞向 Matrigel 塞迁移的能力较低，增殖和血管生成能力较低。此外，免疫组织化学分析显示 MMP8 在内皮细胞在人类动脉粥样硬化斑块和动脉瘤的微脉管系统中表达。最后，对喂食西方饮食 12 周的 MMP8（-/-）/apoE（-/-）和 MMP8（+/+）/apoE（-/-）小鼠进行分析，结果表明 MMP8 缺乏的小鼠的病变较小，动脉粥样硬化病变中的内皮细胞较少。
我们首次证明 MMP8 在体外和体内的血管生成中发挥重要作用。我们的发现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。
