Vascular endothelial growth factor (VEGF) modulates vascular permeability and inflammation in rat brain
Vascular endothelial growth factor (VEGF) modulates vascular permeability and inflammation in rat brain
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DOI：
10.1097/00005072-199906000-00006
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发表时间：
1999-06-01
影响因子：
3.2
通讯作者：
Merrill, MJ
中科院分区：
文献类型：
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作者：
Proescholdt, MA;Heiss, JD;Merrill, MJ
血管内皮生长因子(VEGF)是一种血管生成生长因子，也可诱导血管通透性和巨噬细胞迁移。血管内皮生长因子在正常成人脑中表达较弱，但在胶质瘤细胞和反应性星形胶质细胞中表达强烈上调，提示脑内血管内皮生长因子的慢性过度表达是血脑屏障(BBB)破坏的原因之一。我们用以下方法研究了慢性过度暴露对血脑屏障完整性的影响：1)通过微渗泵持续脑内注射VEGF；2)脑内注射编码VEGF(165)基因的腺病毒载体(AdCMV.VEGF)。6天后，与各自的对照组(白蛋白输注或AdCMV.β-Gal病毒)相比，两种治疗方法产生的BBB LAS崩溃类似于10倍(通过将C-14-氨基异丁酸(AIB)从血液运输到脑中来测量)。在接受AdCMV.VEGF治疗的大脑中，血脑屏障的破坏伴随着一种严重的炎症反应，这在接受AdCMV.beta Gal或VEGF蛋白注射的大脑中没有观察到，这表明无论是VEGF还是病毒颗粒本身都不是炎症反应的罪魁祸首。然而，在同一部位注射AdCMV.beta Gal，然后再注射VEGF，也引起了炎症。正常大脑长期过度暴露于血管内皮生长因子也增加了细胞间黏附分子-1(ICAM-1)和主要组织相容性复合体(MHC)I和II类的表达。虽然血管内皮生长因子本身不是炎症性的，但血管内皮生长因子可能通过开放血脑屏障，改变大脑的免疫保护状态，允许正常隔离的中枢神经系统抗原与血液传播的免疫介质之间的接触来调节中枢神经系统(CNS)的免疫反应。
Vascular endothelial growth factor (VEGF) is an angiogenic growth factor that also induces vascular permeability and macrophage migration. VEGF expression is weak in normal adult brain, but is strongly upregulated in glioma cells and reactive astrocytes, suggesting that chronic overexpression of VEGF in the brain contributes to blood-brain barrier (BBB) breakdown. We examined the effects of chronic VEGF overexposure on the integrity of the BBB using the following approaches: 1) continuous intracerebral infusion of VEGF via miniosmotic pump; and 2) intracerebral injection of an adenoviral vector encoding the VEGF(165) gene (AdCMV.VEGF). After 6 days both treatments produced similar to 10-fold breakdown of the BBB las measured by transport of C-14-aminoisobutyric acid (AIB) from blood into brain) compared with the respective controls (albumin infusion or AdCMV.beta gal virus). BBB disruption in AdCMV.VEGF-treated brains was accompanied by a severe inflammatory response not observed in brains receiving AdCMV.beta gal or VEGF protein infusion, indicating that neither VEGF nor viral particles alone were responsible for the inflammatory response. However, injection of AdCMV.beta gal followed by VEGF infusion to the same site also elicited inflammation. Chronic overexposure of normal brain to VEGF also increased intercellular adhesion molecule-1 (ICAM-1) and major histocompatibility complex (MHC) class I and II expression. Although VEGF itself is not inflammatory, VEGF may modulate immune responses in the central nervous system (CNS) by opening the BBB, altering the immunoprivileged status of the brain, and allowing contact between normally sequestered CNS antigens and blood-borne immune mediators.