A murine model of developmental programming of atherosclerosis



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Early life is increasingly being recognized as an important period of development during which environmental changes can lead to long term effects on an individual’s health. The association between poor nutrition prior to birth and an increased risk to develop coronary heart disease, hypertension and the metabolic syndrome is well established. Animal models are a central tool to investigate the details and mechanistic basis of the effects of the early life milieu. \r\nCoronary artery disease secondary to atherosclerosis remains a major cause of death in most societies. Limited human studies indicate a strong association between maternal hypercholesterolemia and increased rates of formation of atherosclerotic lesions in children. It is conceivable that exposure to a high lipid environment during intrauterine development and early postnatal life may emerge as one of the principal risk factor for premature atherosclerosis.\r\nThese studies were performed to determine the effect of maternal hypercholesterolemia on the risk of atherosclerotic lesion formation in the offspring in a homogenous small animal model. The apoprotein E (apoE)-deficient mouse strain was chosen because of its well described propensity to spontaneously manifest hypercholesterolemia and atherosclerosis. A strong correlation between maternal hypercholesterolemia and an increase in serum cholesterol levels was revealed in chow fed heterozygous litters born to hyperlipidemic dams at both 4 and 8 months of age. In addition, 8-month old heterozygote animals born to apoE-deficient mothers (apoE+/-mat) showed higher rates of atherosclerosis and evidence of liver and kidney damage as compared with their apoE+/-pat counterparts. In contrast, at day 21 of life apoE-/-KO and apoE+/-mat pups showed lower total cholesterol and triglyceride levels than apoE+/+WT or apoE+/-pat litters. \r\nStudies in liver tissue from offspring at 8 months of age suggest activation of the endogenous cholesterol synthetic pathway in apoE+/-mat offspring. This may be one of the mechanisms responsible for the observed programming effects. In-vivo activity and blood pressure measurements and vascular reactivity experiments in 4-month old animals did not demonstrate significant differences among study groups. No marked variation in serum cholesterol levels among genetically similar dams was detected.\r\n



plaque formation, maternal environment, fetus, early life