Platelet-activating factor (PAF) induces activation of matrix metalloproteinase 2 activity and vascular endothelial cell invasion and migration
Platelet-activating factor (PAF) induces activation of matrix metalloproteinase 2 activity and vascular endothelial cell invasion and migration
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DOI：
10.1096/fj.03-0479fje
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发表时间：
2004-01-01
期刊：
影响因子：
4.8
通讯作者：
Hunt, JD
中科院分区：
文献类型：
--
作者：
Axelrad, TW;Deo, DD;Hunt, JD
肿瘤诱导的血管生成反应导致血管内皮细胞中复杂的表型变化，其必须在周围基质的增殖和侵袭之前协调蛋白酶和蛋白酶抑制剂的表达。基质金属蛋白酶2（MMP 2），降解IV型胶原蛋白，产生为proMMP 2。proMMP 2部分地通过其与膜1型MMP（MT 1-MMP）和基质金属蛋白酶组织抑制剂2（TIMP 2）的相互作用而被激活。在这项研究中，我们证明，血小板活化因子（PAF）是一个有效的诱导人脐静脉内皮细胞（HUVEC）的迁移和侵袭，这是由PAF受体拮抗剂衰减，PAF受体拮抗剂抑制前列腺癌细胞系的条件培养基介导的HUVEC的迁移和侵袭。我们证实，PAF受体拮抗剂抑制增殖的HUVEC生长在丰富的生长培养基。我们发现PAF增加MT 1-MMP和TIMP 2的mRNA水平，随后增加潜伏性proMMP 2向MMP 2的时间转换。最后，我们证明，从PAF刺激的HUVEC的膜制备物中的MT 1-MMP与TIMP 2的比例为1.6：1，接近假设的理想比例2：1所需的proMMP 2的MMP 2的转换。我们的数据支持PAF参与血管内皮细胞的迁移和侵袭。
Tumor-induced angiogenic responses lead to complex phenotypic changes in vascular endothelial cells, which must coordinate the expression of both proteases and protease inhibitors prior to the proliferation and invasion of surrounding stroma. Matrix metalloproteinase 2 (MMP2), which degrades Type IV collagen, is produced as proMMP2. proMMP2 is activated in part through its interactions with membrane Type 1 MMP (MT1-MMP) and tissue inhibitor of matrix metalloproteinase 2 (TIMP2). In this study, we demonstrate that platelet-activating factor (PAF) is a potent inducer of human umbilical vein endothelial cell (HUVEC) migration and invasion, which is attenuated by PAF receptor antagonists, and that PAF receptor antagonists inhibit the migration and invasion of HUVEC mediated by medium conditioned by a prostatic carcinoma cell line. We confirm that PAF receptor antagonists inhibit proliferation of HUVEC grown in rich growth medium. We show that PAF increases mRNA levels for MT1-MMP and TIMP2, followed by increased temporal conversion of latent proMMP2 to MMP2. Finally, we demonstrate that the ratio of MT1-MMP to TIMP2 in membrane preparations from PAF-stimulated HUVEC is 1.6:1, approximating the hypothesized ideal ratio of 2:1 necessary for the conversion of proMMP2 to MMP2. Our data support the involvement of PAF in vascular endothelial cell migration and invasion.