Membrane-type matrix metalloproteinase-mediated angiogenesis in a fibrin-collagen matrix
Membrane-type matrix metalloproteinase-mediated angiogenesis in a fibrin-collagen matrix
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DOI：
10.1182/blood-2002-05-1593
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发表时间：
2003-03-01
期刊：
影响因子：
20.3
通讯作者：
van Hinsbergh, VWM
中科院分区：
文献类型：
--
作者：
Collen, A;Hanemaaijer, R;van Hinsbergh, VWM
成人血管生成，与病理条件，往往伴随着形成的恶性渗出液。这种临时基质主要由纤维蛋白组成，但与血浆蛋白和胶原纤维混合。通过体外模型模拟体内血管基质中毛细血管结构的形成，其中在用碱性成纤维细胞生长因子/肿瘤坏死因子α（bFGF/TNF-α）或血管内皮生长因子（VEGF）/TNF-α刺激后，将人微血管内皮细胞（hMVEC）接种在纤维蛋白-10%胶原基质的顶部上形成毛细血管样管状结构。在纤维蛋白-胶原基质中，金属蛋白酶抑制剂BB 94抑制70%至80%的小管形成。抑肽酶和BB 94同时抑制纤溶酶和金属蛋白酶引起几乎完全抑制小管形成。腺病毒转导的组织金属蛋白酶抑制剂1（TIMP-1）和TIMP-3到内皮细胞显示，TIMP-3显着抑制血管生成，而TIMP-1只有轻微的影响。免疫组化分析显示存在基质金属蛋白酶1（MMP-1），MMP-2，和膜型1（MT 1）-MMP，而MMP-9是缺席。通过抗原测定和实时聚合酶链反应（PCR）证实了这些基质金属蛋白酶的内皮生产。MT 1-MMP mRNA在诱导管状结构的条件下在内皮细胞中显著增加。MMP-1、MMP-2和MT 1-MMP的存在也在体内再通动脉附壁血栓的新形成血管中得到证实。这些数据表明，基质金属蛋白酶，特别是MT-MMPS，在体外含胶原纤维蛋白基质中毛细血管样管状结构的形成中起着关键作用，并可能参与体内血管生成的恶性渗出物。
Adult angiogenesis, associated with pathologic conditions, is often accompanied by the formation of a fibrinous exudate. This temporary matrix consists mainly of fibrin but is intermingled with plasma proteins and collagen fibers. The formation of capillary structures in a fibrinous matrix in vivo was mimicked by an in vitro model, in which human microvascular endothelial cells (hMVECs) seeded on top of a fibrin-10% collagen matrix form capillarylike tubular structures after stimulation with basic fibroblast growth factor/tumor necrosis factor alpha (bFGF/TNF-alpha) or vascular endothelial growth factor (VEGF)/TNF-alpha. In the fibrin-collagen matrix the metalloproteinase inhibitor BB94 inhibited tubule formation by 70% to 80%. Simultaneous inhibition of plasmin and metalloproteinases by aprotinin and BB94 caused a nearly complete inhibition of tubule formation. Adenoviral transduction of tissue inhibitor of metalloproteinases 1 (TIMP-1) and TIMP-3 into endothelial cells revealed that TIMP-3 markedly inhibited angiogenesis, whereas TIMP-1 had only a minor effect. Immunohistochemical analysis showed the presence of matrix metalloproteinase 1 (MMP-1), MMP-2, and membrane-type 1 (MT1)-MMP, whereas MMP-9 was absent. The endothelial production of these MMPs was confirmed by antigen assays and real-time polymerase chain reaction (PCR). MT1-MMP mRNA was markedly increased in endothelial cells under conditions that induced tubular structures. The presence of MMP-1, MMP-2, and MT1-MMP was also demonstrated in vivo in the newly formed vessels of a recanalized arterial mural thrombus. These data suggest that MMPs, in particular MT-MMPS, play a pivotal role in the formation of capillarylike tubular structures in a collagen-containing fibrin matrix in vitro and may be involved in angiogenesis in a fibrinous exudate in vivo.