In vitro and in vivo effects of tPA and PAI-1 on blood vessel tone
In vitro and in vivo effects of tPA and PAI-1 on blood vessel tone
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DOI：
10.1182/blood-2003-05-1685
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发表时间：
2004-02-01
期刊：
影响因子：
20.3
通讯作者：
Higazi, AA
中科院分区：
文献类型：
--
作者：
Nassar, T;Akkawi, S;Higazi, AA
组织型纤溶酶原激活物（tPA）是纤溶级联反应中的关键酶。在本文中，我们报告tPA包含2个独立的表位，发挥相反的作用，对血管张力。低浓度的tPA（1 nM）抑制苯丙氨酸（PE）诱导的离体主动脉环收缩。相反，较高浓度（20 nM）刺激PE的收缩作用。tPA的2个推定的血管活性表位由纤溶酶原激活物抑制剂-1（派-1）和结合tPA的派-1衍生的六肽调节。TNK-tPA是派-1对接位点突变的tPA变体，在所有使用的浓度下刺激PE诱导的血管收缩。抗低密度脂蛋白受体相关蛋白/α 2-巨球蛋白受体（LRP）抗体可消除tPA对离体主动脉环收缩的刺激作用，而非抑制作用。对大鼠施用tPA或TNK-tPA以剂量依赖性模式调节血压和脑血管阻力。在其他的体内实验中，我们发现PE的血管加压作用在tPA敲除小鼠中比在野生型小鼠中更明显。我们的研究结果引起了人们对tPA和派-1在调节血管张力中的新作用的关注，这可能会影响缺血性疾病的病程。(C)2004年，美国血液学会。
Tissue type plasminogen activator (tPA) is a key enzyme in the fibrinolytic cascade. In this paper we report that tPA contains 2 independent epitopes that exert opposite effects on blood vessel tone. Low concentrations of tPA (1 nM) inhibit the phenylephrine (PE)-induced contraction of isolated aorta rings. In contrast, higher concentrations (20 nM) stimulate the contractile effect of PE. The 2 putative vasoactive epitopes of tPA are regulated by the plasminogen activator inhibitor-1 (PAI-1) and by a PAI-1-derived hexapeptide that binds tPA. TNK-tPA, a tPA variant in which the PAI-1 docking site has been mutated, stimulates PE-induced vasoconstriction at all concentrations used. The stimulatory, but not the inhibitory, effect of tPA on the contraction of isolated aorta rings was abolished by anti-low-density lipoprotein receptor-related protein/alpha(2)-macroglobulin receptor (LRP) antibodies. Administering tPA or TNK-tPA to rats regulates blood pressure and cerebral vascular resistance in a dose-dependent mode. In other in vivo experiments we found that the vasopressor effect of PE is more pronounced in tPA knockout than in wildtype mice. Our findings draw attention to a novel role of tPA and PAI-1 in the regulation of blood vessel tone that may affect the course of ischemic diseases. (C) 2004 by The American Society of Hematology.