We hypothesize that A_2A adenosine receptor (A_2A AR) activation causes vasorelaxation through cytochrome P450 (CYP)-epoxygenases and EDHFs, whereas, lack of A_2A AR promotes vasoconstriction through Cyp4a in mouse aorta. NECA (10^-6 M), an adenosine-analog, caused relaxation in A_2A AR+/+ (+33.99 ± 4.70%, p<0.05) vs. contraction in A_2AAR-/- (-27.52 ± 4.11%). A_2A AR specific-antagonist (SCH 58261, 1µM), changed NECA (10^-6 M) relaxation response to contraction (-35.82 ± 4.69%, p<0.05) in A_2A AR+/+, while no effect was noted in A_2A AR-/-. Significant contraction was seen in the absence of endothelium in A_2A AR +/+ (E-; -2.58 ± 2.25%) compared to intact (E+). Endothelial NOS (L-NAME, 100µM) & COX inhibitors (indomethacin, 10µM) failed to blocked NECA-induced relaxation in A_2A AR +/+. A selective inhibitor of CYP-epoxygenases (MS-PPOH, 10µM) changed NECA (-22.74± 5.11% at 10^-6 M) and CGS-21680 (-18.54± 6.06% at 10^-6 M) mediated relaxation to contraction in A_2A AR+/+ while no response was noted in A_2A AR-/-. Further, EET antagonist (14,15-EEZE, 10µM) was able to block NECA-induced relaxation in A_2A AR+/+, while -hydroxylase inhibitors (DDMS, 10µM & HET0016, 10µM) changed contraction into relaxation in A_2A AR-/- mice aorta. Cyp2c29 protein was up-regulated in A_2A AR+/+ while Cyp4a was up-regulated in A_2A AR-/-. Higher levels of DHETs (14,15-DHET, 11,12-DHET & 8,9-DHET, p<0.05) were found in A_2A AR+/+ vs. A_2A AR-/-. EETs-levels were not significantly different between A_2A AR+/+ and A_2A AR-/-. It is concluded that CYP-epoxygenases play an important role in A_2A AR-mediated relaxation, and the deletion of A_2A AR leads to contraction through Cyp4a.