Matrix metalloproteinases regulate neovascularization by acting as pericellular fibrinolysins
Matrix metalloproteinases regulate neovascularization by acting as pericellular fibrinolysins
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DOI：
10.1016/s0092-8674(00)81768-7
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发表时间：
1998-10-30
期刊：
影响因子：
64.5
通讯作者：
Weiss, SJ
中科院分区：
文献类型：
--
作者：
Hiraoka, N;Allen, E;Weiss, SJ
在血管生成过程中，内皮细胞通过未知的蛋白分解机制穿透纤维蛋白屏障。我们证明纤溶纤溶酶原激活物(PA)-纤溶酶原系统不是这一过程所必需的，因为从PA或纤溶酶原缺陷小鼠分离的组织成功地使纤维蛋白凝胶新生血管。相比之下，在体外和体内，新生血管的形成依赖于纤溶的内皮细胞衍生的基质金属蛋白酶(MMPs)。MMPs直接调节这一过程，因为当侵袭能力不强的细胞通过纤维蛋白屏障时，当转染内皮细胞中发现的最有效的纤溶金属蛋白酶时，膜类型1基质金属蛋白酶(MT1-MMP)。MT1-MMP膜展示是必需的，因为表达纤溶活性的、跨膜缺失形式的MT1-MMP无侵袭能力的细胞仍然是非侵袭性的。这些观察确定了PA非依赖的纤溶途径，其中拴系的MMPs在新生血管形成过程中作为细胞周围的纤溶蛋白发挥作用。
During angiogenesis, endothelial cells penetrate fibrin barriers via undefined proteolytic mechanisms. We demonstrate that the fibrinolytic plasminogen activator (PA)-plasminogen system is not required for this process, since tissues isolated from PA- or plasminogen-deficient mice successfully neovascularize fibrin gels. By contrast, neovessel formation, in vitro and in vivo, is dependent on fibrinolytic, endothelial cell-derived matrix metalloproteinases (MMP). MMPs directly regulate this process as invasion-incompetent cells penetrate fibrin barriers when transfected with the most potent fibrinolytic metalloproteinase identified in endothelium, membrane type-1 MMP (MT1-MMP). Membrane display of MT1-MMP is required, as invasion-incompetent cells expressing a fibrinolytically active, transmembrane-deleted form of MT1-MMP remain noninvasive. These observations identify a PA-independent fibrinolytic pathway wherein tethered MMPs function as pericellular fibrinolysins during the neovascularization process.