Schoch Heike J, Fischer Silvia, Marti Hugo H
Department of Molecular Cell Biology, Max Planck Institute for Physiological and Clinical Research, Bad Nauheim, Germany.
Brain. 2002 Nov;125(Pt 11):2549-57. doi: 10.1093/brain/awf257.
Formation of cerebral oedema caused by vascular leakage is a major problem in various injuries of the CNS, such as stroke, head injury and high-altitude illness. A common feature of all these disorders is the fact that they are associated with tissue hypoxia. Hypoxia has therefore been suggested to be an important pathogenic factor for the induction of vascular leakage in the brain. Vascular endothelial growth factor (VEGF) is known as the major inducer of angiogenesis. Originally, however, it was described as a vascular permeability factor. As VEGF gene expression was shown to be upregulated by hypoxia, increased VEGF expression may link hypoxia and vascular leakage in the CNS in vivo. To delineate the role of VEGF in vascular leakage in the brain, we studied the effect of hypoxia on VEGF expression and vascular permeability in the brains of mice in vivo. Hypoxic exposure led to a significant increase in the levels of VEGF mRNA and protein in mouse brain that correlated with the severity of the hypoxic stimulus. Measurement of vascular permeability using the fluorescent marker sodium fluorescein revealed a two-fold increase in fluorescence intensity in hypoxic brains, indicative of significant vascular leakage. Inhibition of VEGF activity by a neutralizing antibody completely blocked the hypoxia-induced increase in vascular permeability. In conclusion, our data show that VEGF is responsible for hypoxia-induced augmentation in vascular leakage following tissue hypoxia. Our findings might provide the basis for new therapeutic concepts for the treatment of cerebral oedema.
由血管渗漏引起的脑水肿形成是中枢神经系统各种损伤中的一个主要问题，如中风、头部损伤和高原病。所有这些疾病的一个共同特征是它们都与组织缺氧有关。因此，缺氧被认为是诱导脑内血管渗漏的一个重要致病因素。血管内皮生长因子（VEGF）是已知的血管生成的主要诱导因子。然而，最初它被描述为一种血管通透性因子。由于VEGF基因表达被证明在缺氧时上调，VEGF表达增加可能在体内将中枢神经系统中的缺氧与血管渗漏联系起来。为了阐明VEGF在脑内血管渗漏中的作用，我们在体内研究了缺氧对小鼠脑内VEGF表达和血管通透性的影响。缺氧暴露导致小鼠脑内VEGF mRNA和蛋白水平显著增加，这与缺氧刺激的严重程度相关。使用荧光标记物荧光素钠测量血管通透性显示，缺氧脑内荧光强度增加了两倍，表明存在明显的血管渗漏。用中和抗体抑制VEGF活性完全阻断了缺氧诱导的血管通透性增加。总之，我们的数据表明VEGF是组织缺氧后缺氧诱导的血管渗漏增加的原因。我们的发现可能为治疗脑水肿的新治疗概念提供基础。
