Schulter V, Koolwijk P, Peters E, Frank S, Hrzenjak A, Graier W F, van Hinsbergh V W, Kostner G M
Institute of Medical Biochemistry and Medical Molecular Biology, Karl-Franzens-University, Graz, Austria.
Arterioscler Thromb Vasc Biol. 2001 Mar;21(3):433-8. doi: 10.1161/01.atv.21.3.433.
Angiostatin, which consists of the kringle I-IV domains of plasminogen and which is secreted into urine, is an efficient inhibitor of angiogenesis and tumor growth. Because N-terminal apolipoprotein(a) [apo(a)] fragments, which also contain several types of kringle IV domains, are found in urine as well, we evaluated the potential angiostatic properties of these urinary apo(a) fragments and of a recombinant form of apo(a) [r-apo(a)]. We used human microvascular endothelial cell (hMVEC)-based in vitro assays of tube formation in 3-dimensional fibrin matrixes. Purified urinary apo(a) fragments or r-apo(a) inhibited the basic fibroblast growth factor/tumor necrosis factor-alpha-induced formation of capillary-like structures. At concentrations varying from 0.2 to 10 microgram/mL, urinary apo(a) fragments inhibited tube formation by as much as 70%, whereas there was complete inhibition by r-apo(a). The highest concentrations of both inhibitors also reduced urokinase plasminogen activator production of basic fibroblast growth factor-induced hMVEC proliferation. The inhibitors had no effect on plasminogen activator inhibitor-1 expression. If our in vitro model for angiogenesis is valid for the in vivo situation as well, our data point toward the possibility that apo(a) may also be physiologically operative in modulating angiogenesis, as the concentration of free apo(a) found in humans exceeds that tested herein.
血管抑素由纤溶酶原的kringle I-IV结构域组成，可分泌到尿液中，是一种有效的血管生成和肿瘤生长抑制剂。由于在尿液中也发现了N端载脂蛋白(a)[apo(a)]片段，其也包含几种类型的kringle IV结构域，因此我们评估了这些尿液apo(a)片段以及重组形式的apo(a)[r-apo(a)]的潜在血管抑制特性。我们使用基于人微血管内皮细胞(hMVEC)的三维纤维蛋白基质中管形成的体外试验。纯化的尿液apo(a)片段或r-apo(a)抑制碱性成纤维细胞生长因子/肿瘤坏死因子-α诱导的毛细血管样结构的形成。在0.2至10微克/毫升的浓度范围内，尿液apo(a)片段对管形成的抑制率高达70%，而r-apo(a)则完全抑制。两种抑制剂的最高浓度也降低了碱性成纤维细胞生长因子诱导的hMVEC增殖过程中尿激酶纤溶酶原激活物的产生。这些抑制剂对纤溶酶原激活物抑制剂-1的表达没有影响。如果我们的血管生成体外模型在体内情况也有效，我们的数据表明apo(a)在调节血管生成方面可能也具有生理作用，因为在人类中发现的游离apo(a)浓度超过了本文测试的浓度。
