Department of Cell and Molecular Biology and Pathogenic Bioagents, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14.049-900, Brazil.
Cells. 2019 Apr 12;8(4):349. doi: 10.3390/cells8040349.
Previous studies from our laboratory have shown that during angiogenesis in vitro, rmMCP-7 (recombinant mouse mast cell protease-7) stimulates endothelial cell spreading and induces their penetration into the matrix. The ability of rmMCP-7 to induce angiogenesis in vivo was assessed in the present study using a directed in vivo angiogenesis assay (DIVAA™). Vessel invasion of the angioreactor was observed in the presence of rmMCP-7 but was not seen in the control. Since integrins are involved in endothelial cell migration, the relationship between rmMCP-7 and integrins during angiogenesis was investigated. Incubation with rmMCP-7 resulted in a reduction in the levels of integrin subunits αv and β1 on SVEC4-10 endothelial cells during angiogenesis in vitro. Furthermore, the degradation of integrin subunits occurs both through the direct action of rmMCP-7 and indirectly via the ubiquitin/proteasome system. Even in the presence of a proteasome inhibitor, incubation of endothelial cells with rmMCP-7 induced cell migration and tube formation as well as the beginning of loop formation. These data indicate that the direct degradation of the integrin subunits by rmMCP-7 is sufficient to initiate angiogenesis. The results demonstrate, for the first time, that mMCP-7 acts in angiogenesis through integrin degradation.
先前我们实验室的研究表明，在体外血管生成过程中，rmMCP-7（重组鼠肥大细胞蛋白酶-7）可刺激内皮细胞铺展，并诱导其穿透基质。本研究采用定向体内血管生成测定法（DIVAA™）评估了 rmMCP-7 在体内诱导血管生成的能力。在 rmMCP-7 的存在下观察到了 Angioreactor 中的血管入侵，但在对照中未观察到。由于整合素参与内皮细胞迁移，因此研究了血管生成过程中 rmMCP-7 和整合素之间的关系。体外血管生成过程中，rmMCP-7 孵育导致 SVEC4-10 内皮细胞中整合素亚基 αv 和 β1 的水平降低。此外，整合素亚基的降解既可以通过 rmMCP-7 的直接作用，也可以通过泛素/蛋白酶体系统间接发生。即使存在蛋白酶体抑制剂，rmMCP-7 孵育内皮细胞也会诱导细胞迁移、管状结构形成以及环形成的开始。这些数据表明，rmMCP-7 通过直接降解整合素亚基足以启动血管生成。研究结果首次表明，mMCP-7 通过整合素降解在血管生成中发挥作用。
