Matrix metalloproteinase-19 inhibits growth of endothelial cells by generating angiostatin-like fragments from plasminogen.
Matrix metalloproteinase-19 inhibits growth of endothelial cells by generating angiostatin-like fragments from plasminogen.
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DOI：
10.1186/1471-2091-12-38
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发表时间：
2011-07-25
期刊：
影响因子：
--
通讯作者：
Sedlacek R
中科院分区：
文献类型：
--
作者：
Brauer R;Beck IM;Roderfeld M;Roeb E;Sedlacek R
血管生成是从现有血管形成新血管的过程，需要降解血管基底膜和重塑细胞外基质（ECM），以允许内皮细胞迁移并侵入周围组织。基质金属蛋白酶 (MMP) 被认为在基底膜和 ECM 的重塑中发挥着核心作用。然而，MMP 不仅通过降解 ECM 成分来促进血管重塑。特定的 MMP 通过多种方式增强血管生成；它们帮助周细胞与正在进行血管生成的血管分离，释放ECM结合的血管生成生长因子，暴露ECM中隐秘的促血管生成整合素结合位点，产生前迁移的ECM成分片段，并裂解内皮细胞与细胞之间的粘附。 MMP 还可以通过蛋白水解产生内源性血管生成抑制剂，从而对血管生成过程产生负面影响。血管抑制素是纤溶酶原的蛋白水解片段，是抑制内皮细胞迁移和增殖的最有效的血管生成拮抗剂之一。报告显示，金属弹性蛋白酶、胰腺弹性蛋白酶、纤溶酶还原酶和纤溶酶将纤溶酶原转化为血管抑制素。我们在此报告，MMP-19 以特征性切割模式处理人纤溶酶原，生成三个分子量分别为 35、38 和 42 kDa 的血管抑制素样片段。与对照细胞相比，MMP-19 释放的这些片段显着抑制 HMEC 细胞的增殖 27% (p = 0.01)，并将毛细血管样结构的形成减少 45% (p = 0.05)。众所周知，由于与 HGF 结构相似，血管抑制素可阻断内皮细胞中肝细胞生长因子 (HGF) 诱导的促血管生成信号传导，因此我们分析了 MMP-19 产生的纤溶酶原片段是否干扰该途径。由于它涉及 HGF 受体 c-met 的激活，我们可以证明纤溶酶原的 MMP-19 依赖性加工会降低 c-met 的磷酸化。总而言之，MMP-19 通过生成血管抑制素样片段对内皮细胞表现出抗血管生成作用。
Angiogenesis is the process of forming new blood vessels from existing ones and requires degradation of the vascular basement membrane and remodeling of extracellular matrix (ECM) in order to allow endothelial cells to migrate and invade into the surrounding tissue. Matrix metalloproteinases (MMPs) are considered to play a central role in the remodeling of basement membranes and ECM. However, MMPs contribute to vascular remodeling not only by degrading ECM components. Specific MMPs enhance angiogenesis via several ways; they help pericytes to detach from vessels undergoing angiogenesis, release ECM-bound angiogenic growth factors, expose cryptic pro-angiogenic integrin binding sites in the ECM, generate promigratory ECM component fragments, and cleave endothelial cell-cell adhesions. MMPs can also negatively influence the angiogenic process through generating endogenous angiogenesis inhibitors by proteolytic cleavage. Angiostatin, a proteolytic fragment of plasminogen, is one of the most potent antagonists of angiogenesis that inhibits migration and proliferation of endothelial cells. Reports have shown that metalloelastase, pancreas elastase, plasmin reductase, and plasmin convert plasminogen to angiostatin. We report here that MMP-19 processes human plasminogen in a characteristic cleavage pattern to generate three angiostatin-like fragments with a molecular weight of 35, 38, and 42 kDa. These fragments released by MMP-19 significantly inhibited the proliferation of HMEC cells by 27% (p = 0.01) and reduced formation of capillary-like structures by 45% (p = 0.05) compared with control cells. As it is known that angiostatin blocks hepatocyte growth factor (HGF)-induced pro-angiogenic signaling in endothelial cells due to structural similarities to HGF, we have analyzed if the plasminogen fragments generated by MMP-19 interfere with this pathway. As it involves the activation of c-met, the receptor of HGF, we could show that MMP-19-dependent processing of plasminogen decreases the phosphorylation of c-met. Altogether, MMP-19 exhibits an anti-angiogenic effect on endothelial cells via generation of angiostatin-like fragments.
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影响因子：
11.2
作者：
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