Diabetic vascular dysfunction: Links to glucose‐induced reductive stress and VEGF

Abstract

A complete biochemical understanding of the mechanisms by which hyperglycemia causes vascular functional and structural changes associated with the diabetic milieu still eludes us. In recent years, the numerous biochemical and metabolic pathways postulated to have a causal role in the pathogenesis of diabetic vascular disease have been distilled into several unifying hypotheses. These involve either increased reductive or oxidative stress to the cell, or the activation of numerous protein kinase pathways, particularly protein kinase C and mitogen-activated protein kinases. As detailed below, there is tremendous crosstalk between these competing hypotheses. We propose that increased tissue glucose levels alter cytosolic coenzyme balance by increased flux of glucose through the sorbitol pathway increasing free cytosolic NADH levels. Increased NADH levels can generate reactive oxygen species via numerous mechanisms, lead to the formation of intracellular advanced glycation end products, and induce growth factor expression via mechanisms involving protein kinase C activation. The elevation in growth factors, particularly vascular endothelial growth factor (VEGF), is responsible for the vascular dysfunction via numerous mechanisms reported here in detail.

Advanced glycation end products quench nitric oxide in vitro

“…First, the convincing in vitro demonstration of NO quenching by AGE may not be directly applicable in vivo [24]. Further studies indicate that AGEs can increase NO levels involving increased VEGF production [14,39].…”

Expression of VEGF, iNOS, and eNOS is increased in cochlea of diabetic rat

“…We suggest that there was a causal association between VEGF up-regulation and hyperglycemia in the cochleae of diabetic rats. Many factors influence VEGF expression, including advanced glycation end products (AGEs), high glucose, and oxidative stress [6]. Hyperglycemia could induce the production of AGEs generated by non-enzymatic reactions between glucose and free amino reactive groups of proteins and lipids, and generation of reactive oxygen species (ROS).…”

“…Increased expression of VEGF has been implicated in a variety of disease conditions, including diabetic microvascular disease. Hyperglycemia can directly or indirectly induce VEGF expression [6], which has been considered in the pathogenesis of both diabetic nephropathy and retinopathy. The presence of VEGF and its receptors has been described in the cochlea of different rodents, which possibly regulate vascular permeability and endothelial proliferation in the inner ear [7].…”

Expression profiles of cytokines and chemokines in vitreous fluid in diabetic retinopathy and central retinal vein occlusion

“…Moreover, diabetic macular edema includes not only local edema caused by plasma components leaked from paramacular microaneurysms, but also diffuse edema caused by the breakdown of the blood-retinal barrier [5] and increased paramacular vascular permeability associated with retinal ischemia [6]. Vascular endothelial growth factor (VEGF) and various inflammatory cytokines are thus considered to be involved in increased vascular permeability [7,8].…”