Endothelial cell dysfunction and the vascular complications associated with type 2 diabetes: assessing the health of the endothelium

Abstract

Diabetes-associated vascular complications are collectively the major clinical problems facing patients with diabetes and lead to the considerably higher mortality rate than that of the general population. People with diabetes have a much higher incidence of coronary artery disease as well as peripheral vascular diseases in part because of accelerated atherogenesis. Despite the introduction of new therapies, it has not been possible to effectively reduce the high cardiovascular morbidity and mortality associated with diabetes. Of additional concern is the recognition by the World Health Organization that we are facing a global epidemic of type 2 diabetes. Endothelial dysfunction is an early indicator of cardiovascular disease, including that seen in type 2 diabetes. A healthy endothelium, as defined in terms of the vasodilator/blood flow response to an endothelium-dependent vasodilator, is an important indicator of cardiovascular health and, therefore, a goal for corrective interventions. In this review we explore the cellular basis for endothelial dysfunction in an attempt to identify appropriate new targets and strategies for the treatment of diabetes. In addition, we consider the question of biomarkers for vascular disease and evaluate their usefulness for the early detection of and their role as contributors to vascular dysfunction.

Figure 1

An elevation in plasma glucose brought on by the combined effects of diet, lifestyle, and genes leads to hyperglycemia. Hyperglycemia decreases endothelial nitric oxide synthase (eNOS) activity and thus reduces the bioavailability of nitric oxide (NO) and also increases oxidative stress (enhanced production of $•{\text{O}}_2^{-}$) via, potentially, a multitude of pathways that may include the involvement of mitochondria, NADPH oxidase, xanthine oxidase, cytochrome P450, cyclooxygenase, and lipoxygenase. Oxidative stress also further reduces the bioavailability of NO, thus reducing the inhibitory actions of NO on cytochrome P450 and other enzymes that are involved in the elevation of $•{\text{O}}_2^{-}$. Hyperglycemia may have direct or indirect effects to decrease the numbers and/or viability of endothelial progenitor cells (EPCs) and thus reduce postnatal blood vessel repair and enhance the rate of endothelial cell senescence. Asymmetric dimethylmethylarginine (ADMA) is an endogenous inhibitor of eNOS, and the metabolism of ADMA is decreased when oxidative stress is high and thus elevated ADMA will further decrease the bioavailability of NO. Reduced availability of NO, elevated oxidative stress, and reduced levels of endogenous antioxidants add to the proinflammatory stimuli, and plasma and possibly vascular levels of C-reactive protein (CRP) are elevated. CRP has been reported to decrease the stability of mRNA for eNOS, thus further reducing the synthesis of NO. Endothelial dysfunction results from the reduction in the local production/bioavailability of NO and, possibly, changes in the contribution of endothelium-derived hyperpolarizing factor (EDHF) to the regulation of vascular tone.