Institute of Biochemistry, University of Kiel, Kiel, Germany.
BMC Biochem. 2011 Jul 25;12:38. doi: 10.1186/1471-2091-12-38.
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.
血管生成是指从现有血管中形成新血管的过程，需要降解血管基底膜和重塑细胞外基质（ECM），以使内皮细胞迁移并侵入周围组织。基质金属蛋白酶（MMPs）被认为在基底膜和 ECM 的重塑中起核心作用。然而，MMP 不仅通过降解 ECM 成分来促进血管生成。特定的 MMP 通过多种方式促进血管生成；它们有助于周细胞从正在发生血管生成的血管中分离出来，释放 ECM 结合的血管生成生长因子，暴露出 ECM 中隐藏的促血管生成整合素结合位点，生成促迁移的 ECM 成分片段，并裂解内皮细胞-细胞黏附。MMP 还可以通过蛋白水解切割生成内源性血管生成抑制剂来对血管生成过程产生负面影响。纤溶酶原的蛋白水解片段血管抑素是最强的血管生成拮抗剂之一，可抑制内皮细胞的迁移和增殖。有报道称，金属弹性蛋白酶、胰弹性蛋白酶、纤溶酶原还原酶和纤溶酶将纤溶酶原转化为血管抑素。
我们在此报告 MMP-19 以特征性的切割模式处理人纤溶酶原，生成三个分子量为 35、38 和 42 kDa 的血管抑素样片段。与对照细胞相比，MMP-19 释放的这些片段可使 HMEC 细胞的增殖减少 27%（p = 0.01），并使毛细血管样结构的形成减少 45%（p = 0.05）。由于已知血管抑素由于与 HGF 的结构相似，可阻断 HGF 诱导的内皮细胞中的促血管生成信号，我们分析了 MMP-19 产生的纤溶酶原片段是否会干扰此途径。由于该途径涉及 HGF 的受体 c-met 的激活，我们可以证明 MMP-19 依赖性纤溶酶原处理会降低 c-met 的磷酸化。
总之，MMP-19 通过生成血管抑素样片段对内皮细胞表现出抗血管生成作用。
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