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
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Article info
Publication history
Published online: December 23, 2009
Accepted:
December 4,
2009
Received in revised form:
November 2,
2009
Received:
May 25,
2009
Identification
Copyright
© 2009 Elsevier Ireland Ltd. Published by Elsevier Inc. All rights reserved.
