Statins may have favorable effects on endothelial barrier function. The effect of rosuvastatin and simvastatin therapy (10 mg/kg) for 5 weeks on blood-brain barrier (BBB), blood-retinal barrier (BRB), and cardiac muscle permeability of streptozotocin-induced diabetic rats was studied. The size-selective permeability of different vascular beds to a group of fluorescein isothiocyanate dextrans of varying molecular weights was measured. The volume of distribution of 250-, 70-, and 40-kDa dextrans in the cerebral tissue of diabetic rats were significantly increased. The volume of distribution of these dextrans in cerebral tissue was normalized by both statins. Diabetes did not significantly alter the BRB, but both statins decreased the volume of distribution of 70-and 40-kDa dextrans in the retina. The volume of distribution of 40 kDa in cardiac muscle was increased in diabetes, and this change was prevented with statin treatment. Treatment with rosuvastatin and mevalonate (150 mg/kg in drinking water for 5 weeks) did not alter the volume of distribution measurements. We concluded that 1) diabetes in rats is associated with significant changes in the BBB permeability; 2) statin treatment improves the endothelial barrier function in cerebral tissue, retina, and cardiac muscle; and 3) this statin effect could not be attributed to HMGCoA reductase inhibition. Diabetes 54: [2977][2978][2979][2980][2981][2982] 2005 O ne of the sentinel features of atherosclerosis is endothelial cell dysfunction that manifests itself in a variety of ways including poor nitric oxide production, poor vasodilatory response, and increased adhesiveness to leukocytes (1). Another potential endothelial dysfunction commonly observed in diabetes is altered permeability to macromolecules.Diabetes in humans and in animal models has been found to cause significant alterations in endothelial permeability in various vascular beds (2-5). Potential mechanisms underlying the diabetes-related changes in the blood-brain barrier (BBB) include altered expression of key structural and enzymatic proteins, alterations in the lipid composition and fluidity of the membranes, alterations in the neurotransmitter activity, and increased oxidative damage of the endothelial cells (2,6). Another likely contributor to these changes is the activation of protein kinase C that is shown to play an important role in increased permeability of the peripheral and cerebral circulation (7,8). Finally, recent studies have shown that inactivation of the rho-GTPase has a critical role in endothelial barrier function (9,10).Statins are known to have many pleiotropic effects (11). However, the effect of statins on the functional integrity of the microvasculature of diabetic animals has not been well studied. Statins are known to alter endothelial cell function, smooth muscle cell migration and proliferation, and some aspects of vascular inflammation (11). In addition, statins have been shown to improve endothelial barrier permeability in the aorta of Watanabe hyperlipidimic rabbits ...