Fetal programming of atherosclerosis: Possible role of the mitochondria

Abstract 

Growing evidence indicates that being small size at birth from malnutrition is associated with an increased risk of developing type 2 diabetes (T2D), metabolic syndrome and cardiovascular disease in adulthood. Atherosclerosis is common to these aforementioned disorders, and oxidative stress and chronic inflammation are now considered as initiating events in its development, with endothelial cell dysfunction being an early, fundamental step. According to the fetal programming hypothesis, growth-restricted neonates exposed to placental insufficiency exhibit endothelial cell dysfunction very early in life that later on predisposes them to atherosclerosis. Although many investigations have reported early alterations in vascular function in children and adolescents with low birth weight, the mechanisms of such fetal programming of atherosclerosis remain largely unknown. Experimental studies have demonstrated that low birth weight infants are prenatally subjected to conditions of oxidative stress and inflammation that might be involved in the later occurrence of atherosclerosis. Arterial endothelial dysfunction has been encountered in term infants, children and young adults with low birth weight. The loss of appropriate endothelium function with decreased nitric oxide production or activity, manifested as impaired vasodilatation, is considered a basic step in atherosclerosis development and progression. Several lines of evidence indicate that mitochondrial damage is central to this process and that reactive oxygen species (ROS) may act as a double-edged sword. On the one hand, it is well-accepted that the mitochondria are a major source of chronic ROS production under physiological conditions. On the other hand, it is known that ROS generation damages lipids, proteins and mitochondrial DNA, leading to dysregulated mitochondrial function. Elevated mitochondrial ROS production is associated with endothelial cell dysfunction as well as vascular smooth muscle cell proliferation and apoptosis. Smoking, obesity, insulin-resistant T2D, hypercholesterolemia, hyperglycaemia and hypertriglyceridaemia, major, traditional precursors of atherosclerosis, are all linked to mitochondrial dysfunction.

This review focuses on proof of in utero programming resulting from chronic exposure to oxidative stress and inflammation as a cause of atherosclerosis. Endothelial cell dysfunction may be the initial injury arising from adverse antenatal conditions and responsible for the early changes in vascular function seen in children. After considering the critical role of the mitochondria in atherogenesis through endothelial function abnormalities, we propose that placental mitochondrial dysfunction is present in cases of placental insufficiency and may be critical in fetal programming of atherosclerosis.

Keywords: Fetal programming of atherosclerosis, Oxidative stress, Inflammation, Mitochondria, Mitochondrial dysfunction