Maternal Hypercholesterolemia Enhances Atherogenesis in Normocholesterolemic Rabbits, Which Is Inhibited by Antioxidant or Lipid-Lowering Intervention During Pregnancy

Abstract

Abstract-Maternal hypercholesterolemia during pregnancy is associated with a marked increase in aortic fatty streak formation in human fetuses and faster progression of atherosclerosis during normocholesterolemic childhood. However, the mechanisms responsible are unknown, and the contribution of genetic differences is difficult to assess in humans. The goal of this study was to determine whether maternal hypercholesterolemia per se may cause enhanced fatty streak formation in offspring and whether interventions during pregnancy can reduce it. During pregnancy, 1 group of New Zealand White rabbits was fed control chow and 8 groups were fed hypercholesterolemic diets Chol 1 (yielding plasma cholesterol of 153 mg/dL) or Chol 2 (yielding 359 mg/dL) without or with cholestyramine, vitamin E, or both. Offspring (nϭ15 to 25 per group) were killed at birth. Maternal hypercholesterolemia enhanced mean lesion size in the aorta of their offspring at birth from 44Ϯ18ϫ10 3 m 2 per section in controls to 85Ϯ26ϫ10 3 in Chol 1 and 156Ϯ49ϫ10 3 in Chol 2 groups (PϽ0.0001 for both). Cholestyramine or vitamin E treatment of mothers significantly reduced atherosclerosis at birth by up to 39% compared with controls on the same diet. Oxidized fatty acids and malondialdehyde in aortic atherosclerotic lesions and plasma were similarly affected by diets and treatment as atherosclerosis. Our results establish the causal role of hypercholesterolemia and peroxidation in fetal atherogenesis and demonstrate that both lipid-lowering and antioxidant interventions during pregnancy can reduce it. If it can be established that interventions in mothers also affect progression of lesions after birth, this may indicate a novel approach for the prevention of atherosclerosis.

Maternal Low-Protein Diet or Hypercholesterolemia Reduces Circulating Essential Amino Acids and Leads to Intrauterine Growth Restriction

“…Previous studies have observed a correlation between high maternal cholesterol concentrations and enhanced lesions of atherosclerosis in the offspring in rabbits (17,43) and in LDLR Ϫ/Ϫ mice (18). Maternal oxidative stress in a high cholesterol environment may adversely affect the placenta and may directly or indirectly enhance atherosclerotic lesions in the offspring (44).…”

“…Maternal oxidative stress in a high cholesterol environment may adversely affect the placenta and may directly or indirectly enhance atherosclerotic lesions in the offspring (44). Experiments in hypercholesterolemic rabbits have shown that administration of the antioxidant vitamin E during pregnancy resulted in reduced atherosclerotic lesions in the offspring (16,17), indicating that maternal oxidative stress likely plays a role in maternal programming for atherosclerosis. However, given the complexity of metabolic syndrome traits, it is also likely that more than one physiological pathway is involved.…”

“…A concomitant increase in glucocorticoid-inducible enzymes was found in the fetuses of dams on a low-protein diet (15). Studies examining maternal programming for atherosclerosis have found a significant association between maternal hypercholesterolemia and increased atherosclerotic lesions in the offspring in newborn and adult rabbits (16,17), in adult mice (18), and in human fetuses (19) and children (20). Existing evidence for in utero programming from hypercholesterolemia (21) includes increased maternal oxidative stress (22) and an altered adaptive immune response to oxidized LDL (23).…”

Childhood Infection and Endothelial Dysfunction

“…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 model 10,11 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.…”

“…14 Finally, growing evidence in the literature suggests that vascular damage occurs early and is mediated by polyunsaturated fatty acids secondary to a maternal hypercholesterolemic diet. 10,[15][16][17] Nevertheless, it is not clear to what extent proteic undernutrition during pregnancy can affect vascular function. Taken together, to date, there is considerable evidence that the pathogenesis of endothelial dysfunction and atherogenesis in childhood is related to hypercholesterolemia and oxidation-sensitive mechanisms during early stages of human development.…”