Olah M E, Roudabush F L
Department of Pharmacology and Cell Biophysics, College of Medicine, University of Cincinnati, OH 45267, USA.
J Pharmacol Exp Ther. 2000 Jun;293(3):779-87.
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 approximately 20% of that in control cells with an EC(50) value of 0.47 nM, indicative of mediation by the A(2A)AR. Down-regulation 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-fold 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.
血管内皮生长因子（VEGF）是一种内皮细胞有丝分裂原，在胚胎发育和某些病理过程进展中促进血管生成。本研究检测了PC12大鼠嗜铬细胞瘤细胞中腺苷受体（AR）激活对VEGF表达的调控。用AR激动剂CGS21680处理细胞后，VEGF mRNA水平降至对照细胞的约20%，EC（50）值为0.47 nM，表明是由A（2A）AR介导的。用AR拮抗剂ZM241385预处理细胞可消除CGS21680对VEGF mRNA的下调作用。此外，单独使用ZM241385可使VEGF mRNA比基础水平增加2.8倍。核糖核酸酶保护试验表明，CGS21680下调了VEGF（121）、VEGF（165）和VEGF（189）转录本。CGS21680同样降低了VEGF蛋白分泌。在缺氧条件下，用CGS21680预处理后，VEGF mRNA表达降低了85.7%。下调反应似乎主要是由A（2A）AR与G（s）偶联介导的，因为霍乱毒素处理也降低了VEGF表达。A（2A）AR激活后VEGF mRNA稳态水平的降低显然是由于VEGF基因转录速率降低，而不是mRNA稳定性降低。因此，根据细胞类型的不同，腺苷可能对VEGF产生具有抑制作用，这可能对血管发育有影响。
