To date little is known of the interaction between diabetes and gender in the vasculature. Thus, the objective of this study was to investigate whether there is a gender difference in aortic endothelial cell function in streptozotocin (STZ, 65 mg/kg, iv)-induced diabetic rats. The potential roles of superoxide and cyclooxygenase (COX) metabolites in diabetes-induced vascular dysfunction were also studied. Endothelium-dependent vasodilation (EDV) in response to acetylcholine (ACh; 10-8 to 10-5M) was measured in aortic rings precontracted with phenylephrine (PE; 2ı`M) before and after pretreatment with MnTMPyP (10mM), a superoxide scavenger, or indomethacin (indo; 10ı`M), a COX inhibitor. Constrictor response curves to PE (10-8 to 10-5M) were also generated before and after pretreatment with indo. In addition, the level of endothelial nitric oxide synthase (eNOS) mRNA expression was determined using real time RT-PCR. STZ-induced diabetes impaired EDV, but its effect was more pronounced in females. Similarly, eNOS mRNA expression was lower in diabetic animals and the decrease was greater in females than in males. Preincubation with MnTMPyP increased the sensitivity of aortic rings to ACh-induced relaxation only in diabetic rats, and again the effect was greater in females. In controls, indo significantly reduced contraction to PE in females, but in diabetic rats, males demonstrated the greater reduction in PE response. These results suggest the predisposition of female rat aorta to vascular injury in diabetes, possibly via altered NO and superoxide production. Furthermore, COX metabolites also play a role in the vascular reactivity in the diabetic aorta. (Supported by NIH/NIDCR).