Propranolol adrenergic blockade inhibits human brain endothelial cells tubulogenesis and matrix metalloproteinase-9 secretion
Propranolol adrenergic blockade inhibits human brain endothelial cells tubulogenesis and matrix metalloproteinase-9 secretion
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DOI：
10.1016/j.phrs.2009.05.005
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发表时间：
2009-11-01
影响因子：
9.3
通讯作者：
Beliveau, Richard
中科院分区：
文献类型：
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作者：
Annabi, Borhane;Lachambre, Marie-Paule;Beliveau, Richard
最近的临床观察表明，非选择性P-肾上腺素能拮抗剂心得安可能通过靶向血管内皮细胞来抑制血管内皮细胞肿瘤的生长，如婴儿的血管瘤。鉴于人脑微血管内皮细胞(HBMEC)在肿瘤血管生成中作为结构和功能成分的重要作用，我们评估了普萘洛尔是否可以靶向HBMEC的体外血管生成特性。我们发现，来自人脑胶质母细胞瘤和实验性脑肿瘤相关血管的活检组织表达高水平的β2-肾上腺素能受体，这表明在肿瘤血管形成过程中可能发生肾上腺素能适应过程。我们观察到，当HBMEC种植在Matrigel上时，心得安显著减少了体外培养的HBMEC的小管生成。根据Boyden小室的评估，心得安不会降低细胞存活率，也不会改变HBMEC的迁移。酶谱法检测关键的血管生成和细胞外基质降解酶MMP2和MMP9的分泌。心得安显著减少肿瘤促进剂佛波酯12-肉豆蔻酸酯13-醋酸酯治疗后的基质金属蛋白酶-9的分泌，而基质金属蛋白酶-2的分泌没有受到影响。这与基质金属蛋白酶-9基因表达的减少有关，这在一定程度上是由核质稳定因子Hur的核质输出减少所解释的。因此，我们的数据表明普萘洛尔在抑制基质金属蛋白酶-9的分泌和HBMEC的小管生成方面具有选择性作用，这可能会增加心得安的抗血管生成特性。(C)2009爱思唯尔有限公司。保留所有权利。
in recent clinical observation, the growth of endothelial tumors, such as hemangiomas of infancy, was repressed by the non-selective P-adrenergic antagonist propranolol possibly through targeting of the vascular endothelial compartment. As human brain microvascular endothelial cells (HBMEC) play an essential role as structural and functional components in tumor angiogenesis, we assessed whether propranolol could target HBMEC's in vitro angiogenic properties. We found that biopsies from human glioblastoma as well as from experimental brain tumor-associated vasculature expressed high levels of the beta 2-adrenergic receptor, suggesting adrenergic adaptative processes could take place during tumor vascularization. We observed that in vitro tubulogenesis was significantly reduced by propranolol when HBMEC were seeded on Matrigel. Propranolol,as much as 100 mu M, did not reduce cell viability and did not alter HBMEC migration as assessed with Boyden chambers. Secretion of the key angiogenic and extracellular matrix degrading enzymes MMP-2 and MMP-9 was assessed by zymography. Propranolol significantly reduced MMP-9 secretion upon treatment with the tumor-promoting agent phorbol 12-myristate 13-acetate, while secretion of MMP-2 remained unaffected. This was correlated with a decrease in MMP-9 gene expression which is, in part, explained by a decrease in the nucleocytoplasmic export of the mRNA stabilizing factor HuR. Our data are therefore indicative of a selective role for propranolol in inhibiting MMP-9 secretion and HBMEC tubulogenesis which could potentially add to propranolol's anti-angiogenic properties. (C) 2009 Elsevier Ltd. All rights reserved.