Pepper M S, Vassalli J D, Wilks J W, Schweigerer L, Orci L, Montesano R
Departement of Morphology, University Medical Center, Geneva, Switzerland.
J Cell Biochem. 1994 Aug;55(4):419-34. doi: 10.1002/jcb.240550403.
A tightly controlled increase in extracellular proteolysis, restricted both in time and space, is an important component of the angiogenic process, while anti-proteolysis is effective in inhibiting angiogenesis. By focussing on the plasminogen activator (PA)-plasmin system, the objective of the present studies was to assess whether previously described inhibitors of angiogenesis modify bovine microvascular endothelial cell proteolytic properties. We demonstrate that although synthetic angiostatic steroids (U-24067 and U-42129), heparin, suramin, interferon alpha-2a, and retinoic acid are all inhibitors of in vitro angiogenesis, each of these agents has distinct effects on the plasminogen-dependent proteolytic system. Specifically, angiostatic steroids and interferon alpha-2a reduce urokinase-type PA (u-PA) and PA inhibitor-1 activity, while heparin and retinoic acid increase u-PA activity. Suramin reduces cell-associated u-PA activity and greatly increases PAI-1 production at doses which induce monolayer disruption. These findings demonstrate that a spectrum of alterations in extracellular proteolysis is associated with anti-angiogenesis, and that anti-angiogenesis and anti-proteolysis are not necessarily correlated. A reduction in extracellular proteolysis would be expected to reduce invasion, whereas an increase in proteolysis might modulate the activity of inhibitory cytokines, which in turn could reduce endothelial cell proliferation and migration and inhibit angiogenesis. The spectrum of effects on different elements of the PA system observed in response to the agents assessed suggests that the role of modulations in extracellular proteolytic activity in anti-angiogenesis is likely to be varied and complex.
细胞外蛋白水解的严格控制的增加，在时间和空间上均受到限制，是血管生成过程的一个重要组成部分，而抗蛋白水解作用在抑制血管生成方面是有效的。通过聚焦于纤溶酶原激活剂（PA）-纤溶酶系统，本研究的目的是评估先前描述的血管生成抑制剂是否会改变牛微血管内皮细胞的蛋白水解特性。我们证明，尽管合成的血管生成抑制类固醇（U-24067和U-42129）、肝素、苏拉明、干扰素α-2a和视黄酸都是体外血管生成的抑制剂，但这些药物中的每一种对纤溶酶原依赖性蛋白水解系统都有不同的作用。具体而言，血管生成抑制类固醇和干扰素α-2a会降低尿激酶型PA（u-PA）和PA抑制剂-1的活性，而肝素和视黄酸会增加u-PA的活性。苏拉明在诱导单层破坏的剂量下会降低细胞相关的u-PA活性并大大增加PAI-1的产生。这些发现表明，细胞外蛋白水解的一系列改变与抗血管生成相关，并且抗血管生成和抗蛋白水解不一定相关。细胞外蛋白水解的减少预计会减少侵袭，而蛋白水解的增加可能会调节抑制性细胞因子的活性，这反过来又可能减少内皮细胞的增殖和迁移并抑制血管生成。在所评估的药物作用下观察到的对PA系统不同成分的一系列影响表明，细胞外蛋白水解活性调节在抗血管生成中的作用可能是多样且复杂的。
