Langlois Stéphanie, Gingras Denis, Béliveau Richard
Laboratoire de Médecine Moléculaire Ste-Justine-Université du Québec à Montréal, Centre de Cancérologie Charles-Bruneau, Hôpital Ste-Justine et Université du Québec à Montréal, Montréal, QC, Canada.
Blood. 2004 Apr 15;103(8):3020-8. doi: 10.1182/blood-2003-08-2968. Epub 2003 Dec 11.
Membrane type 1-matrix metalloproteinase (MT1-MMP) has been suggested to play an important role in angiogenesis, but the mechanisms involved remain incompletely understood. Using an in vitro model of angiogenesis in which cell migration of bovine aortic endothelial cells (BAECs) and their morphogenic differentiation into capillary-like structures on Matrigel are induced by overexpression of MT1-MMP, we show that the platelet-derived bioactive lipid sphingosine 1-phosphate (S1P) is the predominant serum factor essential for MT1-MMP-dependent migration and morphogenic differentiation activities. In the presence of S1P, MT1-MMP-dependent cell migration and morphogenic differentiation were inhibited by pertussis toxin, suggesting the involvement of Gi-protein-coupled receptor-mediated signaling. Accordingly, cotransfection of BAECs with MT1-MMP and a constitutively active Galphai2 (Q205L) mutant increased cell migration and morphogenic differentiation, whereas treatment of BAECs overexpressing MT1-MMP with antisense oligonucleotides directed against S1P1 and S1P3, the predominant S1P receptors, significantly inhibited both processes. These results demonstrate that MT1-MMP-induced migration and morphogenic differentiation involve the cooperation of the enzyme with platelet-derived bioactive lipids through S1P-mediated activation of Galphai-coupled S1P1 and S1P3 receptors. Given the important contribution of platelets to tumor angiogenesis, the stimulation of endothelial MT1-MMP function by S1P may thus constitute an important molecular event linking hemostasis to angiogenesis.
1型膜基质金属蛋白酶（MT1-MMP）被认为在血管生成中起重要作用，但其涉及的机制仍未完全清楚。利用一种血管生成的体外模型，其中通过MT1-MMP的过表达诱导牛主动脉内皮细胞（BAECs）的细胞迁移及其在基质胶上向毛细血管样结构的形态发生分化，我们发现血小板衍生的生物活性脂质鞘氨醇1-磷酸（S1P）是MT1-MMP依赖性迁移和形态发生分化活性所必需的主要血清因子。在S1P存在的情况下，百日咳毒素抑制了MT1-MMP依赖性细胞迁移和形态发生分化，提示Gi蛋白偶联受体介导的信号传导参与其中。相应地，BAECs与MT1-MMP和组成型活性Galphai2（Q205L）突变体共转染增加了细胞迁移和形态发生分化，而用针对主要的S1P受体S1P1和S1P3的反义寡核苷酸处理过表达MT1-MMP的BAECs则显著抑制了这两个过程。这些结果表明，MT1-MMP诱导的迁移和形态发生分化涉及该酶与血小板衍生的生物活性脂质通过S1P介导的Galphai偶联的S1P1和S1P3受体激活的协同作用。鉴于血小板对肿瘤血管生成的重要贡献，S1P对内皮MT1-MMP功能的刺激可能因此构成将止血与血管生成联系起来的重要分子事件。
