Rakic J M, Maillard C, Jost M, Bajou K, Masson V, Devy L, Lambert V, Foidart J M, Noël A
Department of Ophthalmology, CHU, Sart-Tilman, 4000 Liège, Belgium.
Cell Mol Life Sci. 2003 Mar;60(3):463-73. doi: 10.1007/s000180300039.
New blood formation or angiogenesis has become a key target in therapeutic strategies aimed at inhibiting tumor growth and other diseases associated with neovascularization. Angiogenesis is associated with important extracellular remodeling involving different proteolytic systems among which the plasminogen system plays an essential role. It belongs to the large serine proteinase family and can act directly or indirectly by activating matrix metalloproteinases or by liberating growth factors and cytokines sequestered within the extracellular matrix. Migration of endothelial cells is associated with significant upregulation of proteolysis and, conversely, immunoneutralization or chemical inhibition of the system reduces angiogenesis in vitro. On the other hand, genetically altered mice developed normally without overt vascular anomalies indicating the possibility of compensation by other proteases in vivo. Nevertheless, they have in some experimental settings revealed unanticipated roles for previously characterized proteinases or their inhibitors. In this review, the complex mechanisms of action of the serine proteases in pathological angiogenesis are summarized alongside possible therapeutic applications.
新的血液形成或血管生成已成为旨在抑制肿瘤生长及其他与新血管形成相关疾病的治疗策略中的关键靶点。血管生成与涉及不同蛋白水解系统的重要细胞外重塑相关，其中纤溶酶原系统起着至关重要的作用。它属于大型丝氨酸蛋白酶家族，可通过激活基质金属蛋白酶或释放隔离在细胞外基质中的生长因子和细胞因子直接或间接发挥作用。内皮细胞的迁移与蛋白水解的显著上调相关，相反，该系统的免疫中和或化学抑制在体外可减少血管生成。另一方面，基因改变的小鼠正常发育，无明显血管异常，这表明体内其他蛋白酶可能具有补偿作用。然而，在某些实验环境中，它们揭示了先前已鉴定的蛋白酶或其抑制剂出人意料的作用。在本综述中，总结了丝氨酸蛋白酶在病理性血管生成中的复杂作用机制以及可能的治疗应用。
