The JAK/STAT pathway is activated in vitro by angiotensin II (ANG II) and endothelin-1 (ET-1), which are implicated in the development of diabetic complications. We hypothesized that ANG II and ET-1 activate the JAK/STAT pathway in vivo to participate in the development of diabetic vascular complications. Using male Sprague-Dawley rats we performed a time course study (days 7, 14 and 28 post-STZ injection) to determine changes in phosphorylation of JAK2, STAT1 and STAT3 in thoracic aorta using standard Western blot techniques. On day 7 there was no change in phosphorylation of JAK2, STAT1 and STAT3. Phosphorylation of JAK2, STAT1 and STAT3 significantly increased on days 14 and 28 and was inhibited by treatment with candesartan (AT1 receptor antagonist, 10 mg/kg/day, orally in drinking water), atrasentan (ETA receptor antagonist, 10 mg/kg/day, orally in drinking water) and AG490 (JAK2 inhibitor, 5 mg/kg/day, ip). On day 28, treatment with all inhibitors prevented the significant increase in systolic blood pressure (tail cuff) of STZ-induced diabetic rats (SBP mmHg: 157± 9.0, 130±3.3, 128±6.8, 131±10.4, STZ, STZ-candesartan, STZ-atrasentan and STZ-AG490 treated respectively). In isolated tissue bath studies, diabetic rats displayed impaired endothelium-dependent relaxation in aorta (maximal relaxation: 95.3%±3.0, 92.6% ± 7.4, 76.9% ± 12.1, 38.3% ± 13.1; Sham, Sham & AG490, STZ & AG490, STZ respectively). Treatment of rats with AG490 restored endothelium-dependent relaxation in aorta from diabetic rats at 14 and 28 days of treatment. These results demonstrate that JAK2 activation in vivo participates in the development of vascular complications associated with STZ-induced diabetes.