I.c.v ADMINISTRATION OF AN ENDOTHELIN ETB RECEPTOR AGONIST STIMULATES VASCULAR ENDOTHELIAL GROWTH FACTOR-A PRODUCTION AND ACTIVATES VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTORS IN RAT BRAIN
I.c.v ADMINISTRATION OF AN ENDOTHELIN ETB RECEPTOR AGONIST STIMULATES VASCULAR ENDOTHELIAL GROWTH FACTOR-A PRODUCTION AND ACTIVATES VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTORS IN RAT BRAIN
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DOI：
10.1016/j.neuroscience.2011.05.058
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发表时间：
2011-09-29
期刊：
影响因子：
3.3
通讯作者：
Tanaka, K.
中科院分区：
文献类型：
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作者：
Koyama, Y.;Nagae, R.;Tanaka, K.
血管内皮生长因子 (VEGF) 是血管生成因子家族，神经损伤时会上调。为了阐明大脑中 VEGF 产生所涉及的细胞外信号，我们检查了血管收缩肽家族内皮素 (ET) 的作用。 I.c.v.给予 500 pmol/d Ala(1,3,11,15)-ET-1（一种 ETB 受体激动剂）可增加大鼠大脑中 VEGF-A mRNA 的水平，而 VEGF-B、胎盘生长因子（PLGF）、血管生成素（ANG）-1 和 ANG-2 mRNA 的水平则不受 Ala(1,3,11,15)-ET 的显着影响。通过同时给予 1 nmol/d BQ788（一种 ETB 拮抗剂），可以减少 ET 诱导的大脑 VEGF-A mRNA 的增加。 Ala(1,3,11,15)-ET-1 还刺激大脑中 VEGF-A 蛋白的产生。 Ala(1,3,11,15)-ET-1 输注大鼠大脑中的免疫组织化学观察表明，胶质纤维酸性蛋白 (GFAP) 阳性星形胶质细胞具有 VEGF-A 免疫反应性。 Ala(1,3,11,15)-ET-1 输注大鼠的神经元、小胶质细胞和脑毛细血管内皮细胞没有表现出 VEGF-A 反应性。 i.c.v.给予Ala(1,3,11,15)-ET-1刺激大鼠大脑中VEGF-R1和R2受体的酪氨酸磷酸化，而总VEGF-R1和R2蛋白的表达水平没有太大变化。酪氨酸磷酸化 VEGF-R1 的免疫反应性选择性地显示在 Ala(1,3,11,15)-ET-1 输注大鼠大脑中的 GFAP 阳性星形胶质细胞中。酪氨酸磷酸化的 VEGF-R2 蛋白存在于星形胶质细胞和脑毛细血管内皮细胞中。这些发现表明，大脑 ETB 受体的激活会增加 VEGF-A 的产生并刺激大脑中的 VEGF 受体信号传导。 (C) 2011 国际广播组织。由爱思唯尔有限公司出版。保留所有权利。
Vascular endothelial growth factors (VEGFs), a family of angiogenic factors, are upregulated by nerve injuries. To clarify the extracellular signals involved in VEGF production in the brain, the effects of endothelins (ETs), a family of vasoconstricting peptides, were examined. I.c.v. administration of 500 pmol/d Ala(1,3,11,15)-ET-1, an ETB receptor agonist, increased the level of VEGF-A mRNA in the rat cerebrum, whereas those of VEGF-B, placental growth factor (PLGF), angiopoietin (ANG)-1, and ANG-2 mRNAs were not largely affected by Ala(1,3,11,15)-ET. The ET-induced increases in cerebrum VEGF-A mRNA were reduced by coadministration of 1 nmol/d BQ788, an ETB antagonist. Ala(1,3,11,15)-ET-1 also stimulated the production of VEGF-A proteins in the cerebrum. Immunohistochemical observations in the cerebrum of Ala(1,3,11,15)-ET-1-infused rats showed that glial fibrillary acidic protein (GFAP)-positive astrocytes had VEGF-A immunoreactivity. Neurons, microglia, and brain capillary endothelial cells in the Ala(1,3,11,15)-ET-1-infused rats did not show VEGF-A reactivity. The i.c.v. administration of Ala(1,3,11,15)-ET-1 stimulated tyrosine phosphorylations of VEGF-R1 and R2 receptors in the rat cerebrum, whereas expression levels of total VEGF-R1 and R2 proteins were not largely changed. Immunoreactivity of tyrosine-phosphorylated VEGF-R1 was selectively shown in GFAP-positive astrocytes in the cerebrum of Ala(1,3,11,15)-ET-1-infused rats. Tyrosine-phosphorylated VEGF-R2 proteins were present in astrocytes and brain capillary endothelial cells. These findings indicate that activation of brain ETB receptors increases production of VEGF-A and stimulates VEGF receptor signaling in the brain. (C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.