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.