Down-regulation of vascular endothelial growth factor expression after A_2A adenosine receptor activation in PC12 pheochromocytoma cells

作     者：Olah, ME Roudabush, FL 

作者机构：Univ Cincinnati Coll Med Dept Pharmacol & Cell Biophys Cincinnati OH 45267 USA 

出 版 物：《JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS》 (药理学与实验治疗学杂志)

年 卷 期：2000年第293卷第3期

页      面：779-787页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 10[医学] 

基　　金：NCI NIH HHS [R01 CA79531-01] Funding Source: Medline 

主　　题：腺苷/类似物和衍生物 腺苷/药理学 减量调节 内皮生长因子/遗传学 基因表达调控 淋巴因子/遗传学 PC12细胞 苯乙胺类/药理学 RNA 信使/分析 受体 嘌呤能P1/生理学 信号传导 三嗪类/药理学 三唑类/药理学 血管内皮生长因子A 血管内皮生长因子类 动物 大鼠 

摘      要：Vascular endothelial growth factor (VEGF) is an endothelial cell mitogen that promotes angiogenesis during embryonic development and the progression of certain pathologies. This study examined the regulation of VEGF expression by adenosine receptor (AR) activation in PC12 rat pheochromocytoma cells. Treatment of cells with the AR agonist CGS21680 reduced the VEGF mRNA level to similar to 20% of that in control cells with an EC50 value of 0.47 nM, indicative of mediation by the A(2A)AR. Downregulation of VEGF mRNA by CGS21680 was abolished by pretreatment of cells with the AR antagonist ZM241385. Additionally, ZM241385 alone increased VEGF mRNA by 2.8-foId above basal. RNase protection assays indicated that CGS21680 down-regulated VEGF(121), VEGF(165), and VEGF(189) transcripts. VEGF protein secretion was similarly decreased by CGS21680. Under hypoxic conditions, VEGF mRNA expression was reduced by 85.7% after pretreatment with CGS21680. The down-regulation response appears to be mediated predominately by coupling of the A(2A)AR to G(s) because cholera toxin treatment also reduced VEGF expression. The decrease in VEGF mRNA steady-state levels after A(2A)AR activation is apparently due to a decrease in the VEGF gene transcription rate and not to a decrease in mRNA stability. Thus, depending on the cell type, adenosine may have an inhibitory effect on VEGF production, which may have implications in blood vessel development.