Down-regulation of vascular endothelial growth factor expression after A(2A) adenosine receptor activation in PC12 pheochromocytoma cells

Vascular endothelial growth factor (VEGF) is an endothelial cell mitogen th at promotes angiogenesis during embryonic development and the progression o f certain pathologies. This study examined the regulation of VEGF expressio n by adenosine receptor (AR) activation in PC12 rat pheochromocytoma cells. Treatment of cells with the AR agonist CGS21680 reduced the VEGF mRNA leve l 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 CGS 21680 was abolished by pretreatment of cells with the AR antagonist ZM24138 5. 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 resp onse appears to be mediated predominately by coupling of the A(2A)AR to G(s ) because cholera toxin treatment also reduced VEGF expression. The decreas e in VEGF mRNA steady-state levels after A(2A)AR activation is apparently d ue 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.