Diabetes is characterized with increased oxidant stress, vasculopathy, and neuropathy. In diabetic vasculopathy, the observed thickening of the media and intima is not only a result of vascular smooth muscle cell proliferation but also due to modification of the extracellular matrix by these cells. Also, there is hampered membrane function and a reduction in sodium pump expression in the vessels of the diabetic animals. Selenium, being a trace element, has both insulinomimetic and antioxidant effects. Thus, we hypothesized that selenium treatment will reduce proliferation, restore physiology, and correct increased proliferation signaling of diabetic aorta. Diabetes was induced by streptozotocin (50 mg/kg body weight), and rats were then treated with sodium selenate (15 μmol/kg body weight/day) for 4 weeks. Our data from diabetic rats showed an increase in proliferation rate and matrix metalloproteinase activity in aortic cell cultures. We observed marked increases in MAPK phosphorylation and caveolin 1 expression but a decrease in Na +/K+ ATPase activity in diabetic rat aorta homogenates. Selenium treatment resulted in complete normalization of the above parameters to control level, while it increased Na+/K+ pump activity by 40%. Our results suggest that selenium treatment of diabetics can play beneficial role in protecting vascular architecture and function against diabetes-induced pathology. © 2008 Humana Press Inc.