Endothelial Dysfunction: Is There a Hyperglycemia-Induced Imbalance of NOX and NOS?

Abstract

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.

Higher levels of daily physical activity are associated with better skin microvascular function in type 2 diabetes—The Maastricht Study

“…The associations of higher levels of total and higher‐intensity physical activity with greater heat‐induced skin hyperemia in individuals with T2D are in agreement with findings from priorhuman and animal research . As in individuals with T2D insulin sensitivity is thought to be worse, a likely explanation for stronger associations in T2D is that in T2D physical activity improves nitric oxide bioavailability via both stimulation of eNOS and inhibition of eNOS uncoupling . Alternatively, as in individuals NGM insulin sensitivity is not reduced, the effect of physical activity on nitric oxide bioavailability may be less strong because under normal glycemic circumstances physical activity is thought to mostly improve nitric oxide bioavailability via stimulation of eNOS …”

“…Mechanistically, higher levels of physical activity and lower levels of sedentary time are thought to increase nitric oxide bioavailability . On the one hand, physical activity is thought to induce microvascular laminar shear stress and thereby stimulate the synthesis of nitric oxide by endothelial nitric oxide synthase (eNOS) . On the other hand, physical activity is thought to inhibit eNOS uncoupling via reduction of oxidative stress by improvement of insulin sensitivity …”

Endothelial dysfunction in neuroprogressive disorders—causes and suggested treatments

“…This structure allows the transfer of electrons from NADPH to the haem site where the bound oxygen is reduced before being incorporated into arginine to form NO and citrulline [256,257]. Crucially, BH 4 is an indispensable cofactor in this reaction [258], reviewed in [259].…”

Cellular Senescence as the Pathogenic Hub of Diabetes-Related Wound Chronicity

“…Chronic low-grade inflammation and an increased burden of senescent cells are hallmarks of aging in diabetic subjects (10). Hyperglycemia per se is known to act as a senescence-promoting factor for cultured cells (39, 40), and steadily precipitates organs complications and functional demise by different mechanistic pathways (10,(41)(42)(43)(44).…”