Maternal Hypercholesterolemia and Treatment During Pregnancy Influence the Long-Term Progression of Atherosclerosis in Offspring of Rabbits

Abstract

Abstract-Maternal hypercholesterolemia during pregnancy is associated with enhanced fatty streak formation in human fetuses and faster progression of atherosclerosis during childhood even under normocholesterolemic conditions. A causal role of maternal hypercholesterolemia in lesion formation during fetal development has previously been established in rabbits. The same experimental model is now used to establish that maternal hypercholesterolemia or ensuing pathogenic events in fetal arteries enhance atherogenesis later in life. Five groups of rabbit mothers were fed chow, cholesterol-enriched chow, or cholesterol-enriched chow plus 1000 IU vitamin E, 3% cholestyramine, or both during pregnancy. Offspring of all groups (nϭ136) were fed a mildly hypercholesterolemic diet for up to a year and had similar cholesterol levels. Aortic lesion sizes and lipid peroxidation products in plasma and lesions in offspring were determined at birth, 6 months, or 12 months. Lesion progression in offspring of hypercholesterolemic mothers was greater than in all other groups. At each time point, offspring of hypercholesterolemic mothers had 1.5-to 3-fold larger lesions than offspring of normocholesterolemic mothers (PϽ0.01), with the greatest absolute differences at 12 months. Maternal treatment reduced lesions by 19% to 53%, compared with offspring of untreated hypercholesterolemic mothers (PϽ0.01), with the greatest effect in the vitamin E groups. At 12 months, lesions in offspring of all vitamin E and cholestyramine-treated mothers were similar to those of normocholesterolemic mothers. Lipid peroxidation end-products in lesions and plasma showed analogous differences between groups as lesions (PϽ0.01). Thus, pathogenic programming in utero increases the susceptibility to atherogenic risk factors later in life and maternal intervention with cholesterol-lowering drugs or antioxidants reduce postnatal lipid peroxidation and atherosclerosis in their offspring.

Predictive Adaptive Responses to Maternal High-Fat Diet Prevent Endothelial Dysfunction but Not Hypertension in Adult Rat Offspring

“…[11][12][13][14][15]19 The present study investigated whether any or all of the cardiovascular defects described previously in adult rats exposed during pregnancy and suckling to a diet rich in lard 14 could be prevented if the rats were fed the same diet in adulthood, ie, to investigate the role of predictive adaptive responses. Remarkably, the defect in endothelial function in male and female offspring of rats exposed prenatally and during suckling to the fat-rich diet and maintained from weaning on standard chow was absent when the offspring were fed the fat-rich diet.…”

“…Rodents exposed in early development to maternal protein deprivation 4 -6 or maternal global dietary restriction [7][8][9][10] demonstrate insulin resistance and hypertension in adulthood when maintained on a balanced diet. Developmental programming of adulthood cardiovascular and metabolic disorders in animals is, however, not limited to dietary restriction, because we and others have shown that exposure to a maternal diet rich in saturated fat [11][12][13][14] or cholesterol 15 also results in features of the metabolic syndrome, vascular dysfunction, and vascular atherogenic lesions in adult animals raised on standard chow.…”

Parental influence on children's early eating environments and obesity risk: implications for prevention

“…The epigenetic processes that begin with maternal obesity have a greater impact on those who are already genetically susceptible to obesity. 47,48 When rats predisposed (DIO) and resistant (DR) to diet-induced obesity were exposed to maternal obesity during gestation, the DIO offspring were fatter postnatally. 48 The maternal diet during pregnancy can also influence offspring eating behaviors and weight through effects on the development of food and flavor preferences in humans.…”

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

“…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).…”