Department of Obstetrics and Gynaecology, Université de Montréal, Research Centre, CHU Sainte-Justine, Montreal, Quebec, Canada.
Eur J Obstet Gynecol Reprod Biol. 2010 Apr;149(2):127-30. doi: 10.1016/j.ejogrb.2009.12.005. Epub 2010 Jan 6.
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.
越来越多的证据表明，出生时因营养不良而体型较小与成年后患 2 型糖尿病（T2D）、代谢综合征和心血管疾病的风险增加有关。动脉粥样硬化是这些疾病的共同特征，氧化应激和慢性炎症现在被认为是其发展的起始事件，内皮细胞功能障碍是早期的基本步骤。根据胎儿编程假说，暴露于胎盘功能不全的生长受限新生儿在生命早期就表现出内皮细胞功能障碍，随后使他们易患动脉粥样硬化。尽管许多研究报告了低出生体重儿童和青少年血管功能的早期改变，但这种胎儿编程导致动脉粥样硬化的机制在很大程度上仍不清楚。实验研究表明，低出生体重婴儿在产前就处于氧化应激和炎症的状态，这可能与后来发生动脉粥样硬化有关。在足月婴儿、儿童和低出生体重的年轻成年人中已经遇到了动脉内皮功能障碍。一氧化氮产生或活性减少导致适当的内皮功能丧失，表现为血管舒张受损，被认为是动脉粥样硬化发展和进展的基本步骤。有几条证据表明，线粒体损伤是这个过程的核心，活性氧（ROS）可能是一把双刃剑。一方面，众所周知，线粒体在生理条件下是慢性 ROS 产生的主要来源。另一方面，已知 ROS 的产生会损害脂质、蛋白质和线粒体 DNA，导致线粒体功能失调。升高的线粒体 ROS 产生与内皮细胞功能障碍以及血管平滑肌细胞增殖和凋亡有关。吸烟、肥胖、胰岛素抵抗型 T2D、高胆固醇血症、高血糖和高三酰甘油血症，是动脉粥样硬化的主要、传统的前体，都与线粒体功能障碍有关。这篇综述重点介绍了由于慢性暴露于氧化应激和炎症而导致的宫内编程是动脉粥样硬化的原因的证据。内皮细胞功能障碍可能是由不良的产前条件引起的初始损伤，是儿童血管功能早期变化的原因。在考虑了通过内皮功能异常导致动脉粥样硬化的线粒体在动脉粥样硬化形成中的关键作用后，我们提出胎盘线粒体功能障碍存在于胎盘功能不全的情况下，并且可能对胎儿编程导致的动脉粥样硬化至关重要。
