ADAM12 and ADAM17 are essential molecules for hypoxia-induced impairment of neural vascular barrier function.
ADAM12 and ADAM17 are essential molecules for hypoxia-induced impairment of neural vascular barrier function.
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DOI：
10.1038/srep12796
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发表时间：
2015-08-05
影响因子：
4.6
通讯作者：
Ikeda E
中科院分区：
文献类型：
--
作者：
Cui D;Arima M;Takubo K;Kimura T;Horiuchi K;Minagawa T;Matsuda S;Ikeda E
神经血管屏障是多细胞生物体生存所必需的，组织缺氧对神经血管屏障的损伤是导致各种难治性神经系统疾病进展的重要病理生理学基础。因此，参与缺氧诱导的血管屏障损伤的分子可以成为建立新的治疗顽固性疾病的靶点。在这里，我们表明，解整合素和金属蛋白酶（亚当斯）12和17在内皮细胞中表达的分子负责缺氧损伤神经血管屏障。脑微血管内皮细胞在体外缺氧刺激后，通过减少细胞膜上紧密连接分子claudin-5的定位，立即失去了屏障特性。通过抑制金属蛋白酶活性完全抑制了细胞膜中紧密连接蛋白-5的低渗消失和随之而来的屏障性质的丧失，发现金属蛋白酶活性的抑制归因于ADAM 12和ADAM 17。ADAM 12或ADAM 17的抑制足以拯救缺氧下的体内神经血管系统免于屏障功能的丧失。这是第一个报告，以指定的分子，负责缺氧诱导的神经血管屏障的损害，并进一步可能成为新的治疗策略的目标，为难治性神经疾病。
Neural vascular barrier is essential for the life of multicellular organisms, and its impairment by tissue hypoxia is known to be a central of pathophysiology accelerating the progression of various intractable neural diseases. Therefore, the molecules involved in hypoxia-induced impairment of vascular barrier can be the targets to establish new therapies for intractable diseases. Here, we demonstrate that a disintegrin and metalloproteinases (ADAMs) 12 and 17 expressed in endothelial cells are the molecules responsible for the impairment of neural vascular barrier by hypoxia. Brain microvascular endothelial cells in vitro lost their barrier properties immediately after hypoxic stimulation through diminished localization of claudin-5, a tight junction molecule, on cell membranes. Hypoxic disappearance of claudin-5 from cell membranes and the consequent loss of barrier properties were completely suppressed by inhibition of the metalloproteinase activity which was found to be attributed to ADAM12 and ADAM17. Inhibition of either ADAM12 or ADAM17 was sufficient to rescue the in vivo neural vasculature under hypoxia from the loss of barrier function. This is the first report to specify the molecules which are responsible for hypoxia-induced impairment of neural vascular barrier and furthermore can be the targets of new therapeutic strategies for intractable neural diseases.