Abstract 11569: Activation of cAMP/CREB/PGC-1α Pathway Plays a Key Role for a Novel Adenosine-like Angiogenic Agent COA-Cl to Induce Production of Vascular Endothelial Growth Factor (VEGF) in Cultured Human Fibroblasts

COA-Cl is a recently developed pro-angiogenic agent (Figure) that promotes tube forming activity of human umbilical vein endothelial cells that are co-cultured with fibroblasts. Recently, a metabolic stress-related co-transcription factor termed PGC-1α was identified as a novel activator of VEGF gene, a key regulator of angiogenesis. In skeletal muscle, the cAMP/CREB signaling pathway plays a central role in inducing PGC-1α expression. We therefore hypothesized that COA-Cl induces PGC-1α to promote VEGF production by elevating cAMP and activating CREB in fibroblasts. COA-Cl (100 μM for 48 h) augmented VEGF secretion into culture medium of normal human dermal fibroblasts from below the level of detection to 54±4 pg/mL (ELISA, p<0.01 vs. basal). This enhancement of VEGF secretion was associated with up-regulation of mRNA encoding VEGF and PGC-1α (RT-PCR, 2.1±0.3 and 9.9±0.8 fold, p<0.05, respectively). Induction of PGC-1α expression by COA-Cl was attenuated by 49±4% (p<0.01 vs. COA-Cl alone) by H-89 (100 μM...