Background Endothelial dysfunction contributes to the development of atherosclerosis in patients with diabetes mellitus, but the mechanisms of endothelial dysfunction in this setting are incompletely understood. Recent studies have shown altered mitochondrial dynamics in diabetes mellitus with increased mitochondrial fission and production of reactive oxygen species (ROS). We investigated the contribution of altered dynamics to endothelial dysfunction in diabetes. Methods and Results We observed mitochondrial fragmentation (P=0.002) and increased expression of fission-1 protein (Fis1, P<0.0001) in venous endothelial cells freshly isolated from patients with diabetes mellitus (n=10) compared to healthy controls (n=9). In cultured human aortic endothelial cells exposed to 30 mM glucose, we observed a similar loss of mitochondrial networks and increased expression of Fis1 and dynamin-related protein-1 (Drp1), proteins required for mitochondrial fission. Altered mitochondrial dynamics was associated with increased mitochondrial ROS production and a marked impairment of agonist-stimulated activation of endothelial nitric oxide synthase (eNOS) and cGMP production. Silencing Fis1 or DRP1 expression with siRNA blunted high glucose-induced alterations in mitochondrial networks, ROS production, eNOS activation, and cGMP production. An intracellular ROS scavenger provided no additional benefit, suggesting that increased mitochondrial fission may impair endothelial function via increased ROS. Conclusions These findings implicate increased mitochondrial fission as a contributing mechanism for endothelial dysfunction in diabetic states.

Objectives-Sedentary lifestyle increases the risk of cardiovascular disease and diabetes. Vascular dysfunction contributes to atherogenesis and has been linked to insulin resistance. Methods and Results-We measured insulin sensitivity by glucose tolerance test and vascular function by ultrasound and venous occlusion plethysmography in 20 healthy subjects (14 men, 6 women) at baseline and during 5 days of bed rest.Bed rest led to a 67% increase in the insulin response to glucose loading (PϽ0.001) suggesting increased insulin resistance and produced increases in total cholesterol and triglycerides. Bed rest led to decreased reactive hyperemia in the forearm (1317Ϯ404 to 1112Ϯ260 mL/min, Pϭ0.01) and the calf (28.5Ϯ7.0 to 22.2Ϯ8.7 mL/min/dL, Pϭ0.003) indicating impaired microvascular function. Bed rest decreased brachial artery diameter and increased systolic blood pressure suggesting increased basal arterial tone. There were no changes in circulating inflammatory markers arguing against systemic inflammation as a mechanism for vascular dysfunction in this setting. Conclusions-Physical inactivity was associated with the development of insulin resistance, dyslipidemia, increased blood pressure, and impaired microvascular function in healthy volunteers. 3 Despite compelling evidence that physical inactivity is detrimental to cardiovascular health, over one quarter of all Americans engage in no leisure time physical activity. 4 The pathways leading from a sedentary lifestyle to insulin resistance and atherosclerosis are incompletely understood.Dysfunction of the vascular endothelium contributes to atherogenesis 5 and has been linked to sedentary lifestyle. In cross-sectional studies, sedentary individuals have impaired endothelial vasomotor function compared with those who are physically active. 6 Sedentary individuals also display impaired reactive hyperemia, 7 which is the increase in blood flow that occurs after transient ischemia and is a complex response that reflects both endothelium-dependent and endothelium-independent dilation of resistance vessels. 8 States of insulin resistance, including type 2 diabetes mellitus and obesity, are also associated with endothelial dysfunction. 9 Previous studies have demonstrated that short periods of inactivity lead to insulin resistance in humans. 10 -12 We hypothesized that insulin resistance induced by short-term physical inactivity would be associated with vascular dysfunction. This finding would lend further support to basic studies suggesting that insulin resistance and vascular dysfunction share common mechanisms. 13 Thus, we assessed vascular function and glucose tolerance before and after a 5-day period of strict bed rest in healthy subjects. Materials and Methods SubjectsHealthy nonsmoking volunteers were recruited for this study by newspaper and internet advertisement. Subjects were eligible if they had no clinical history of hypertension, diabetes mellitus, or hyperlipidemia, and were not taking any prescription medications. We sought individuals with preserved ...

Chronic cranberry juice consumption reduced carotid femoral pulse wave velocity-a clinically relevant measure of arterial stiffness. The uncontrolled pilot study suggested an acute benefit; however, no chronic effect on measures of endothelial vasodilator function was found. This trial was registered at clinicaltrials.gov as NCT00553904.