Endothelial dysfunction and diabetes: effects on angiogenesis, vascular remodeling, and wound healing

Abstract

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by inappropriate hyperglycemia due to lack of or resistance to insulin. Patients with DM are frequently afflicted with ischemic vascular disease or wound healing defect. It is well known that type 2 DM causes amplification of the atherosclerotic process, endothelial cell dysfunction, glycosylation of extracellular matrix proteins, and vascular denervation. These complications ultimately lead to impairment of neovascularization and diabetic wound healing. Therapeutic angiogenesis remains an attractive treatment modality for chronic ischemic disorders including PAD and/or diabetic wound healing. Many experimental studies have identified better approaches for diabetic cardiovascular complications, however, successful clinical translation has been limited possibly due to the narrow therapeutic targets of these agents or the lack of rigorous evaluation of pathology and therapeutic mechanisms in experimental models of disease. This paper discusses the current body of evidence identifying endothelial dysfunction and impaired angiogenesis during diabetes.

Figure 1

Diabetic vascular disease effects and symptoms. Various pathophysiological conditions affected in the body due to diabetic vascular disease are illustrated. Prominent symptoms of diabetes mediated abnormalities are indicated for each condition.

Figure 2

Hyperglycemic effects on the blood vessel. Atherosclerotic plaque formation initiated through uptake of LDL from blood by endothelial cells. Foam cells produce proinflammatory cytokines that are released into the lumen of blood vessel (far right). Increased ROS production through iNOS leads to increased ROS generation. Steps involved in leukocyte adhesion and migration (bottom left). Increased glucose leads to decreased L-arginine and BH4, which leads to decreased NO production in endothelial cells. All of these factors are proinflammatory and atherogenic.

Figure 3

Signaling mechanisms leading to endothelial dysfunction under diabetes. Diabetes-mediated hyperglycemia leads to multiple-signal pathway dysfunction within vascular endothelial cells. Primary insults include mitochondrial dysfunction, defective PI3 kinase signaling, decreased NO production, increased oxidative stress, and differential PKC isoform activation. Key words: pARP: poly (ADP-ribose) polymerase; AGE: advance glycation end products; DAG: diacylglycerol; NF-κB: nuclear factor kappa-B; PKC: protein kinase C; iNOS: inducible nitric oxide synthase; NADH: nicotinamide adenine dinucleotide; NO: nitric oxide; RAGE: receptor for advanced glycation endproducts; O₂ ^∙: superoxide anion; ONOO⁻: peroxynitrite; PI3K: phosphatidylinositol 3-kinases; AKT: protein kinase B; eNOS: endothelial nitric oxide synthase; GTPCH: GTP cyclohydrolase; BH4: tetrahydrobiopterin; BH2: dihydrobiopterin.