Intrauterine Exposure to Maternal Atherosclerotic Risk Factors Increases the Susceptibility to Atherosclerosis in Adult Life

Abstract

Objective-Maternal hypercholesterolemia is associated with a higher incidence and faster progression of atherosclerotic lesions in neonatal offspring. We aimed to determine whether an in utero environment exposing a fetus to maternal hypercholesterolemia and associated risk factors can prime the murine vessel wall to accelerated development of cardiovascular disease in adult life. Methods and Results-To investigate the epigenetic effect in utero, we generated genetically identical heterozygous apolipoprotein E-deficient progeny from mothers with a wild-type or apolipoprotein E-deficient background. A significant increase in loss of endothelial cell volume was observed in the carotid arteries of fetuses of apolipoprotein E-deficient mothers, but fatty streak formation was absent. Spontaneous atherosclerosis development was absent in the aorta and carotid arteries in adult life. We unilaterally placed a constrictive collar around the carotid artery to induce lesion formation. In offspring from apolipoprotein E-deficient mothers, collar placement resulted in severe neointima formation in 9 of 10 mice analyzed compared with only minor lesion volume (2 of 10) in the progeny of wild-type mothers. Conclusions-We conclude that the susceptibility to neointima formation of morphologically normal adult arteries is already imprinted during prenatal development and manifests itself in the presence of additional atherogenic risk factors in adult life. Future research will concentrate on the mechanisms involved in this priming process, as well as on prevention strategies. Key Words: atherosclerosis Ⅲ carotid arteries Ⅲ pregnancy Ⅲ risk factors Ⅲ hypercholesterolemia P ostnatal risk factors of atherosclerosis are well defined, and mechanisms contributing to lesion formation are increasingly understood. Previous studies showed that the atherogenic process in humans can already start during fetal development. 1 In a morphometric postmortem analysis of atherosclerosis in fetuses and children (Fate of Early Lesions in Children Study), 2 it was demonstrated that specifically maternal hypercholesterolemia was associated with a higher incidence of atherosclerotic lesions during the fetal period and a faster progression of these atherosclerotic lesions after birth even under conditions of normocholesterolemia in the offspring. A causal role for maternal hypercholesterolemia in fetal lesion formation was demonstrated in a genetically nonhomogeneous rabbit model of diet-induced hypercholesterolemia and confirmed in a low-density lipoprotein receptor-deficient mouse model (Ldlr Ϫ/Ϫ ). 3,4 Raised cholesterol intake of pregnant Ldlr Ϫ/Ϫ mice accelerated the progression of spontaneous atherosclerotic lesions in the Ldlr Ϫ/Ϫ progeny. Because these mice have elevated plasma cholesterol levels independent of the maternal cholesterol levels during postnatal life, they are genetically prone to develop atherosclerotic lesions. The question remains whether solely environmental atherogenic risk factors present in utero can prime the developing vascu...

Site Specificity of Aneurysmal Disease

“…59 The possibility that maternal risk factors play a role in aneurysmal disease has received little attention. In view of evidence that in utero factors can program arterial gene expression in later life, regional differences in hemodynamic conditions could have a similar effect.…”

Dyslipidemia of Mothers With Familial Hypercholesterolemia Deteriorates Lipids in Adult Offspring

“…21 Moreover, plaque formation was increased in offspring born to hypercholesterolemic dams. 14,21 In a human study, the effects of exposure to diabetes in utero were evaluated in the macrosomic offspring of both diabetic and healthy mothers. The diabetic mothers had significantly higher total and LDL-C levels (219.8 versus 146.5 mg/dL) compared with the healthy mothers, and their macrosomic offspring had significantly higher LDL-C levels than macrosomic neonates of healthy mothers (126.1 versus 74.2 mg/dL).…”

“…11 There are also indications that, besides hyperglycemia, maternal hypercholesterolemia may increase the risk for CVD in the offspring. [12][13][14][15] A recent study showed that adult mice born to hypercholesterolemic dams had an increased transcriptional activity of both genes involved in the cholesterol synthesis and LDLR in the liver. 15 In humans, fatty streak formation progressed strikingly faster in children of hypercholesterolemic mothers than in those of normocholesterolaemic mothers, 16 but the longterm consequences in humans are still controversial.…”

Vascular Dysfunction in Women with Recurrent Pregnancy Loss

“…Intrauterine exposure to maternal atherosclerotic risk factors may increases the susceptibility to atherosclerosis in adult life (Alkemade et al, 2007). In a morphometric postmortem analysis of atherosclerosis in fetuses and children (Fate of Early Lesions in Children Study), it is demonstrated that specifically maternal hypercholesterolemia is associated with a higher incidence of atherosclerotic lesions during the fetal period and a faster progression of these atherosclerotic lesions after birth even under conditions of normocholesterolemia in the offspring (Napoli et al, 1999).…”