Vitamin D is known to elicit a vasoprotective effect, while vitamin D deficiency is a risk factor for endothelial dysfunction (ED). ED is characterized by reduced bioavailability of a potent endothelium-dependent vasodilator, nitric oxide (NO), and is an early event in the development of atherosclerosis. In endothelial cells, vitamin D regulates NO synthesis by mediating the activity of the endothelial NO synthase (eNOS). Under pathogenic conditions, the oxidative stress caused by excessive production of reactive oxygen species (ROS) facilitates NO degradation and suppresses NO synthesis, consequently reducing NO bioavailability. Vitamin D, however, counteracts the activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase which produces ROS, and improves antioxidant capacity by enhancing the activity of antioxidative enzymes such as superoxide dismutase. In addition to ROS, proinflammatory mediators such as TNF-α and IL-6 are risk factors for ED, restraining NO and eNOS bioactivity and upregulating the expression of various atherosclerotic factors through the NF-κB pathway. These proinflammatory activities are inhibited by vitamin D by suppressing NF-κB signaling and production of proinflammatory cytokines. In this review, we discuss the diverse activities of vitamin D in regulating NO bioavailability and endothelial function.

NADPH oxidases (NOX) are enzyme complexes that have received much attention as key molecules in the development of vascular dysfunction. NOX have the primary function of generating reactive oxygen species (ROS), and are considered the main source of ROS production in endothelial cells. The endothelium is a thin monolayer that lines the inner surface of blood vessels, acting as a secretory organ to maintain homeostasis of blood flow. The enzymatic production of nitric oxide (NO) by endothelial NO synthase (eNOS) is critical in mediating endothelial function, and oxidative stress can cause dysregulation of eNOS and endothelial dysfunction. Insulin is a stimulus for increases in blood flow and endothelium-dependent vasodilation. However, cardiovascular disease and type 2 diabetes are characterized by poor control of the endothelial cell redox environment, with a shift toward overproduction of ROS by NOX. Studies in models of type 2 diabetes demonstrate that aberrant NOX activation contributes to uncoupling of eNOS and endothelial dysfunction. It is well-established that endothelial dysfunction precedes the onset of cardiovascular disease, therefore NOX are important molecular links between type 2 diabetes and vascular complications. The aim of the current review is to describe the normal, healthy physiological mechanisms involved in endothelial function, and highlight the central role of NOX in mediating endothelial dysfunction when glucose homeostasis is impaired.

Creatine is a naturally occurring compound, functioning in conjunction with creatine kinase to play a quintessential role in both cellular energy provision and intracellular energy shuttling. An extensive body of literature solidifies the plethora of ergogenic benefits gained following dietary creatine supplementation; however, recent findings have further indicated a potential therapeutic role for creatine in several pathologies such as myopathies, neurodegenerative disorders, metabolic disturbances, chronic kidney disease and inflammatory diseases. Furthermore, creatine has been found to exhibit non-energy-related properties, such as serving as a potential antioxidant and anti-inflammatory. Despite the therapeutic success of creatine supplementation in varying clinical populations, there is scarce information regarding the potential application of creatine for combatting the current leading cause of mortality, cardiovascular disease (CVD). Taking into consideration the broad ergogenic and non-energy-related actions of creatine, we hypothesize that creatine supplementation may be a potential therapeutic strategy for improving vascular health in at-risk populations such as older adults or those with CVD. With an extensive literature search, we have found only four clinical studies that have investigated the direct effect of creatine on vascular health and function. In this review, we aim to give a short background on the pleiotropic applications of creatine, and to then summarize the current literature surrounding creatine and vascular health. Furthermore, we discuss the varying mechanisms by which creatine could benefit vascular health and function, such as the impact of creatine supplementation upon inflammation and oxidative stress.

Introduction: A family history of type 2 diabetes (FH+) is a major risk factor for the development of insulin resistance and type 2 diabetes. However, it remains unknown whether exercise-induced improvements in insulin sensitivity and metabolic flexibility are impacted by a FH+. Therefore, we investigated whether improvements in insulin sensitivity, metabolic flexibility, body composition, aerobic fitness and muscle strength are limited by a FH+ following eight weeks of combined exercise training compared to individuals without a family history of type 2 diabetes (FH–). Methods: Twenty (n = 10 FH–, n = 10 FH+) young, healthy, sedentary, normoglycemic, Mexican-American males (age: FH– 22.50 ± 0.81, FH+ 23.41 ± 0.86 years; BMI: FH– 27.91 ± 1.55, FH+ 26.64 ± 1.02 kg/m²) underwent eight weeks of combined aerobic and resistance exercise training three times/week (35 min aerobic followed by six full-body resistance exercises). Insulin sensitivity was assessed via hyperinsulinemic euglycemic clamps. Metabolic flexibility was assessed by the change in respiratory quotient from fasted to insulin-stimulated states. Body composition was determined using dual-energy x-ray absorptiometry. Aerobic fitness was determined by a graded exercise test, and upper- and lower-body strength were assessed via one-repetition maximum bench press and leg strength dynamometer, respectively. Results: Insulin sensitivity, metabolic flexibility, aerobic fitness and strength were not different between groups (p > 0.05). Eight weeks of combined aerobic and resistance exercise training improved insulin sensitivity (FH– p = 0.02, FH+ p = 0.002), increased fat free mass (FH– p = 0.006, FH+ p = 0.001), aerobic fitness (FH– p = 0.03, FH+ p = 0.002), and upper- (FH– p = 0.0001, FH+ p = 0.0001) and lower-body strength (FH– p = 0.0009, FH+ p = 0.0003), but did not change metabolic flexibility (p > 0.05) in both groups. Exercise-induced improvements in metabolic outcomes were similar between groups. Conclusions: Insulin sensitivity, metabolic flexibility, aerobic fitness and strength were not compromised by a FH+. Additionally, a FH+ is not a limiting factor for exercise-induced improvements in insulin sensitivity, aerobic fitness, body composition, and strength in normoglycemic young Mexican-American men.

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Impaired blood flow and elevated reactive oxygen species (ROS) concentrations, generated primarily from NADPH oxidase (NOX), indicate risk for cardiovascular disease (CVD). Creatine monohydrate (CM) may reduce CVD risk by lowering ROS concentrations and increasing skeletal muscle microvascular blood flow (SMBF). To determine if NOX-derived ROS impairs SMBF and whether five days of CM supplementation reduces in-vivo ROS concentrations and improves SMBF. Seven individuals had two microdialysis probes placed (control (CON) and apocynin (APO): NOX inhibitor) in skeletal muscle to measure in-vivo ROS (Hydrogen Peroxide (H₂O₂)) concentrations and SMBF (ethanol outflow/inflow ratio, inversely related to blood flow) at rest and four hours post-meal consumption. Procedures were performed before (PRE) and after (POST) five days of CM supplementation (20 g/day). Dialysate H₂O₂ concentrations were lower in the APO probe compared to CON from 120–140 min (APO: 1.19 ± 0.39 µM; CON: 2.04 ± 0.95 µM, p = 0.039), 140–160 min (APO: 1.17 ± 0.37 µM; CON: 2.06 ± 0.98 µM, p = 0.034) and 160–180 min post meal ingestion (p ≤ 0.05). APO perfusion increased SMBF at 20–40 min, 120–140 min (APO: 0.61 ± 0.13; CON: 0.75 ± 0.09 µM, p = 0.048), 140–160 min (APO: 0.61 ± 0.12 µM; CON: 0.76 ± 0.14 µM, p = 0.046), 160–180 min, and 180–200 min post meal (p ≤ 0.05). Ethanol outflow/inflow ratio was lower (higher SMBF) POST CM supplementation compared to PRE CM supplementation at 0–20 min (p = 0.036) and 20–40 min (p = 0.049) following HC/HF meal consumption. Inhibition of NOX-derived ROS increased SMBF, suggesting that NOX activity may impair blood flow regulation over the duration of baseline and post-prandial time points. Further, CM supplementation could be an effective strategy for enhancing postprandial blood flow.