Childhood Infection and Endothelial Dysfunction

Abstract

The prodromal stage of atherosclerotic lesions (known as lipidotic fatty streak accumulation) is already formed during human fetal development.1 Fatty streaks containing characteristic accumulations of lipids, lipid peroxidation products, and macrophages occur in the aorta of premature fetuses. Intimal thickening is also observed in fetal coronary arteries.2,3 During infancy, fatty streaks become increasingly prevalent, and some of them progress to advanced stages of atherosclerotic lesions.4–7 Once initiated, the progression of atherosclerosis is influenced by classic risk factors that promote vascular inflammation and plaque rupture. The observation that maternal hypercholesterolemia is associated with greatly enhanced fatty streak formation in fetal arteries1 indicates that hypercholesterolemia may play a pathogenic role in early fetal atherosclerotic lesions. Maternal hypercholesterolemia is also able to influence fetal sterol metabolism during pregnancy in animal models.8,9 Consistently, direct evidence for a causal role of maternal hypercholesterolemia and the involvement of oxidative stress has been obtained in a rabbit model10,11 and in LDL receptor–deficient mice.12 From a molecular standpoint, many signaling pathways are affected by increased oxidation of LDL or the intracellular formation of reactive oxygen species, and this phenomenon can be exacerbated by concomitant hypercholesterolemia.13 Interestingly, deletion of the p66 shc longevity gene reduces systemic and tissue oxidative stress, vascular cell apoptosis, and early atherogenesis in mice fed a very highly hypercholesterolemic diet.14 Finally, growing evidence in the literature suggests that vascular damage occurs early and is mediated by …