Assessment of endothelial dysfunction in childhood obesity and clinical use

Abstract

The association of obesity with noncommunicable diseases, such as cardiovascular complications and diabetes, is considered a major threat to the management of health care worldwide. Epidemiological findings show that childhood obesity is rapidly rising in Western society, as well as in developing countries. This pandemic is not without consequences and can affect the risk of future cardiovascular disease in these children. Childhood obesity is associated with endothelial dysfunction, the first yet still reversible step towards atherosclerosis. Advanced research techniques have added further insight on how childhood obesity and associated comorbidities lead to endothelial dysfunction. Techniques used to measure endothelial function were further brought to perfection, and novel biomarkers, including endothelial progenitor cells, were discovered. The aim of this paper is to provide a critical overview on both in vivo as well as in vitro markers for endothelial integrity. Additionally, an in-depth description of the mechanisms that disrupt the delicate balance between endothelial damage and repair will be given. Finally, the effects of lifestyle interventions and pharmacotherapy on endothelial dysfunction will be reviewed.

Figure 1

Normal endothelial function versus endothelial dysfunction. Schematic overview of nitric oxide (NO) production and relaxation of Vascular Smooth Muscle Cells (VSMC). In response to increased shear stress or as a result of insulin signaling, the phosphoinositol 3 kinase (PI3K)/akt pathway is activated leading to phosphorylation of endothelial Nitric Oxide Synthase (eNOS). eNOS, together with the necessary cofactor tetrahydrobiopterin (BH₄), converts L-arginine to L-citrulline and NO. NO activates guanylyl cyclase, which induces smooth muscle relaxation, through increased production of cyclic Guanosine MonoPhosphate (cGMP). Superoxide reduced NO bioavailability by reacting with NO to form peroxynitrite (ONOO⁻), which has strong oxidant properties. Endothelial dysfunction in obese children is characterized by insulin resistance impairing insulin-mediated NO production and subsequent vasodilation. Furthermore, oxidized LDL and ADMA are inhibitors of eNOS activation. In the situation of diminished availability of BH₄, eNOS becomes “uncoupled” and paradoxically leads to increased reactive oxygen species (ROS) generation, which also contributes to reduced bioavailability of NO and vasoconstriction. ADMA, Asymmetric DiMethylArginine; PI3K, PhosphatidylInositol 3-Kinase; BH₄, tetrahydrobiopterin; eNOS, endothelial Nitric Oxide Synthase; O₂ ⁻, superoxide; ONOO⁻, peroxynitrite; GTP, Guanosine TriPhosphate; cGMP, cyclic Guanylyl MonoPhosphate; NADPH oxidase, Nicotinamide Adenine Dinucleotide Phosphate oxidase; OxLDL, Oxidized Low-Density Lipoprotein Cholesterol.

Figure 2

Mechanisms involved in endothelial damage and repair. Upon activation endothelial cells express adhesion molecules (i.e.; VCAM-1 and ICAM-1), which allow leukocytes to adhere, transmigrate, and initiate a cascade of inflammatory reactions and the release of EMP into the circulation. With significant endothelial damage, cells become senescent and are detached. This ultimately leads to the recruitment of CAC, monocyte-macrophage-derived cells that contribute to vascular repair by adhering to loci of endothelial damage, and producing angiogenic cytokines that induce the mobilization of EPC from the bone marrow. The angiogenic cytokines produced by CAC also serve as homing molecules with a chemotactic effect on EPC. As a consequence, EPC migrate to damaged endothelium and eventually integrate into the endothelial cell layer. Besides being released after endothelial activation, EMPs also contributes to endothelial homeostasis by cytoprotective effects on endothelial cells, including reduced apoptosis. EC, Endothelial Cell; VSMC, Vascular Smooth Muscle Cell; VCAM-1, Vascular Cell Adhesion Molecule 1; ICAM-1, InterCellular Adhesion Molecule 1; EMP, Endothelial MicroParticles; CAC, Circulating Angiogenic Cells; EPC, Endothelial Progenitor Cells.