Croll Susan D, Ransohoff Richard M, Cai Ning, Zhang Qing, Martin Francis J, Wei Tao, Kasselman Lora J, Kintner Jennifer, Murphy Andrew J, Yancopoulos George D, Wiegand Stanley J
Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA.
Exp Neurol. 2004 Jun;187(2):388-402. doi: 10.1016/j.expneurol.2004.02.010.
Vascular endothelial growth factor (VEGF) has been shown to induce angiogenesis when infused continuously into adult rat brain tissue. In addition, VEGF has been shown to enhance permeability in brain vasculature. Adult rats were continuously infused with mouse VEGF into neocortex for up to 7 days. We studied the development of VEGF-induced vasculature in rat neocortex and evaluated the temporal expression of a wide variety of markers for inflammation and vascular leak in relation to the angiogenic response using immunohistochemistry and Western blot analysis. We report here that VEGF-mediated inflammation in brain is characterized by upregulation of ICAM-1 and the chemokine MIP-1alpha, as well as a preferential extravasation of monocytes. VEGF causes a dramatic breakdown of the blood-brain barrier, which is characterized by decreased investment of the vasculature with astroglial endfeet. Perivascular cells, in contrast, increase around the newly formed cerebrovasculature. In addition, breakdown of the blood-brain barrier, leukocyte extravasation, and extracellular matrix deposition occur before vascular proliferation. Furthermore, administration of low doses of VEGF induces permeability and inflammation without appreciable vascular proliferation.
血管内皮生长因子（VEGF）已被证明，当持续注入成年大鼠脑组织时可诱导血管生成。此外，VEGF已被证明可增强脑血管的通透性。成年大鼠被持续向新皮质注入小鼠VEGF长达7天。我们研究了大鼠新皮质中VEGF诱导的血管系统的发育，并使用免疫组织化学和蛋白质印迹分析评估了与血管生成反应相关的多种炎症和血管渗漏标志物的时间表达。我们在此报告，VEGF介导的脑部炎症的特征是细胞间黏附分子-1（ICAM-1）和趋化因子巨噬细胞炎性蛋白-1α（MIP-1α）上调，以及单核细胞的优先外渗。VEGF导致血脑屏障的显著破坏，其特征是血管周围星形胶质细胞终足的包绕减少。相比之下，新形成的脑血管周围的血管周细胞增加。此外，血脑屏障的破坏、白细胞外渗和细胞外基质沉积发生在血管增殖之前。此外，低剂量VEGF的给药诱导通透性和炎症，而没有明显的血管增殖。
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