Cardiovascular complications, characterized by endothelial dysfunction and accelerated atherosclerosis, are the leading cause of morbidity and mortality associated with diabetes. There is growing evidence that excess generation of highly reactive free radicals, largely due to hyperglycemia, causes oxidative stress, which further exacerbates the development and progression of diabetes and its complications. Overproduction and/or insufficient removal of these free radicals result in vascular dysfunction, damage to cellular proteins, membrane lipids and nucleic acids. Despite overwhelming evidence on the damaging consequences of oxidative stress and its role in experimental diabetes, large scale clinical trials with classic antioxidants failed to demonstrate any benefit for diabetic patients. As our understanding of the mechanisms of free radical generation evolves, it is becoming clear that rather than merely scavenging reactive radicals, a more comprehensive approach aimed at preventing the generation of these reactive species as well as scavenging may prove more beneficial. Therefore, new strategies with classic as well as new antioxidants should be implemented in the treatment of diabetes.

The risk of cerebrovascular disease is four-to sixfold higher in patients with diabetes. Vascular remodeling, characterized by extracellular matrix deposition and an increased media-to-lumen ratio, occurs in diabetes and contributes to the development of complications. However, diabetes-induced changes in the cerebrovascular structure remain unknown. Endothelin-1 (ET-1), a potent vasoconstrictor with profibrotic properties, is chronically elevated in diabetes. To determine diabetesmediated changes in the cerebrovasculature and the role of ET-1 in this process, type 2 diabetic GotoKakizaki (GK) rats were administered an ET A receptor antagonist for 4 weeks. Middle cerebral arteries were harvested and studies were performed to determine vascular structure. Tissue and plasma ET-1 levels were increased in GK rats compared with controls. Significant medial hypertrophy and collagen deposition resulted in an increased wall-to-lumen ratio in diabetic rats that was reduced by ET A receptor antagonism. Vascular matrix metalloproteinase (MMP)-2 activity was higher, but MMP-1 levels were significantly reduced in GK rats, and MMP levels were restored to control levels by ET A receptor antagonism. We conclude that ET-1 promotes cerebrovascular remodeling in type 2 diabetes through differential regulation of MMPs. Augmented cerebrovascular remodeling may contribute to an increased risk of stroke in diabetes, and ET A receptor antagonism may offer a novel therapeutic target. Diabetes 54:2638 -2644, 2005 T ype 2 diabetes, a disease that affects more than 17 million Americans, holds a two-to sixfold increased risk for cerebrovascular disease and stroke (1,2), and 70% of patients with a recent stroke have overt diabetes or pre-diabetes characterized by impaired fasting glucose or impaired glucose tolerance (3). However, the underlying basis of this predisposition remains unclear. Diabetic vascular complications are associated with remodeling of the vessel wall in the retinal, renal, and mesenteric circulations. However, diabetesinduced structural changes in the cerebral microvessels are unknown.The endothelium is an early target in diabetes, and dysfunction of vascular endothelial cells has a role in the diabetic vascular disease process (4). For example, the release of vasodilator and antiproliferative mediators such as nitric oxide and prostaglandin-I 2 is decreased, whereas production of endothelin-1 (ET-1) is increased (5). A significant correlation has been observed between plasma ET-1 levels and diabetes complications. In addition to being vasoconstrictive, ET-1 is also mitogenic. In streptozotocin-induced diabetes, nonselective ET receptor antagonism prevents extracellular matrix deposition in the retina as well as in the mesenteric arteries, providing evidence for a causal relationship (6,7). Nonselective blockade of ET receptors also prevents increased myogenic tone of cerebral vessels in diabetes (8), but the effect on vascular structure and the underlying mechanisms remain to be identified.The matrix metalloproteinases ...