Extracellular RNA mediates endothelial-cell permeability via vascular endothelial growth factor
Extracellular RNA mediates endothelial-cell permeability via vascular endothelial growth factor
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DOI：
10.1182/blood-2006-08-040691
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发表时间：
2007-10-01
期刊：
影响因子：
20.3
通讯作者：
Preissner, Klaus T.
中科院分区：
文献类型：
--
作者：
Fischer, Silvia;Gerriets, Tibo;Preissner, Klaus T.
细胞损伤导致细胞内物质暴露，并与损伤附近血管通透性增加有关。在这里，我们证明了天然细胞外RNA以及人工RNA (poly-I:C)，或单链RNA而不是DNA，在体外和体内显著增加了脑微血管内皮细胞的通透性。rna诱导的内皮细胞紧密单层的高渗透性与紧密连接的解体相关，并通过血管内皮生长因子（VEGF）介导，使人联想到肝素的活性。抗vegf -受体2 （VEGF-R2）的反义油核苷酸完全阻止细胞外RNA和肝素的通透性诱导活性。因此，这些多阴离子物质可导致VEGF的动员/稳定，随后激活VEGF- r2。根据这些功能数据，可以证明VEGF以及其他生长因子与RNA的强结合。在fecl3诱导的大鼠窦矢状面血栓形成和中风/脑水肿的体内模型中，RNase（而不是DNase）预处理动物导致血管闭塞，梗死体积显著减少，并预防脑水肿的形成。总之，这些结果确定细胞外RNA是一种新的天然通透因子，位于VEGF的上游，而对抗RNase治疗可能作为一种新的血管保护方式。
Cell injury leads to exposure of intracellular material and is associated with increased permeability of vessels in the vicinity of the damage. Here, we demonstrate that natural extracellular RNA as well as artificial RNA (poly-I:C), or single-stranded RNA but not DNA, significantly increased the permeability across brain microvascular endothelial cells in vitro and in vivo. RNA-induced hyperpermeability of tight monolayers of endothelial cells correlated with disintegration of tight junctions and was mediated through vascular endothelial growth factor (VEGF), reminiscent of heparin's activities. Antisense oilgonucleotides against VEGF-receptor 2 (VEGF-R2) prevented the permeability-inducing activity of extracellular RNA and heparin completely. Hence, these polyanionic substances can lead to mobilization/ stabilization of VEGF with the subsequent activation of VEGF-R2. In accordance with these functional data, strong binding of VEGF as well as other growth factors to RNA was demonstrable. In in vivo rat models of FeCl3-induced sinus sagittal is superior thrombosis and stroke/brain edema, pretreatment of animals with RNase (but not DNase) resulted in a significant reduction of vessel occlusion, infarct volume, and prevention of brain edema formation. Together, these results identify extracellular RNA as a novel natural permeability factor, upstream of VEGF, whereas counteracting RNase treatment may serve as new vessel-protective modality.