Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia. Intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions.

Abstract

To determine whether oxidized LDL enhances atherogenesis by promoting monocyte recruitment into the vascular intima, we investigated whether LDL accumulation and oxidation precede intimal accumulation of monocytes in human fetal aortas (from spontaneous abortions and premature newborns who died within 12 h; fetal age 6.2 Ϯ 1.3 mo). For this purpose, a systematic assessment of fatty streak formation was carried out in fetal aortas from normocholesterolemic mothers ( n ϭ 22), hypercholesterolemic mothers ( n ϭ 33), and mothers who were hypercholesterolemic only during pregnancy ( n ϭ 27). Fetal plasma cholesterol levels showed a strong inverse correlation with fetal age ( R ϭ Ϫ 0.88, P Ͻ 0.0001). In fetuses younger than 6 mo, fetal plasma cholesterol levels correlated with maternal ones ( R ϭ 0.86, P ϭ 0.001), whereas in older fetuses no such correlation existed. Fetal aortas from hypercholesterolemic mothers and mothers with temporary hypercholesterolemia contained significantly more and larger lesions (758,651 Ϯ 87,449 and 451,255 Ϯ 37,448 m 2 per section, respectively; mean Ϯ SD) than aortas from normocholesterolemic mothers (61,862 Ϯ 9,555 m 2 ; P Ͻ 0.00005). Serial sections of the arch, thoracic, and abdominal aortas were immunostained for recognized markers of atherosclerosis: macrophages, apo B, and two different oxidation-specific epitopes (malondialdehyde-and 4-hydroxynonenal-lysine). Of the atherogenic sites that showed positive immunostaining for at least one of these markers, 58.6% were established lesions containing both macrophage/foam cells and oxidized LDL (OxLDL). 17.3% of all sites contained only native LDL, and 13.3% contained only OxLDL without monocyte/ macrophages. In contrast, only 4.3% of sites contained isolated monocytes in the absence of native or oxidized LDL. In addition, 6.3% of sites contained LDL and macrophages but few oxidation-specific epitopes. These results demonstrate that LDL oxidation and formation of fatty streaks occurs already during fetal development, and that both phenomena are greatly enhanced by maternal hypercholesterolemia. The fact that in very early lesions LDL and Ox-LDL are frequently found in the absence of monocyte/macrophages, whereas the opposite is rare, suggests that intimal LDL accumulation and oxidation contributes to monocyte recruitment in vivo. ( J. Clin. Invest. 1997. 100:2680-2690.)

Childhood obesity: a life-long health risk

“…The disease accounts for the majority of deaths due to myocardial infarction and stroke in Western as well as in Eastern and developing countries [27] . First vascular abnormalities, inflammatory changes and plaque development can be observed in children already in the first year of life [28] ; consistent with these observations, the disease process begins in utero, during which the precursor of the atherosclerotic plaque -the "fatty streak" -is already present [29,30] . The development of fatty streaks, which represent inflammatory accumulations of macrophages in the subintimal space -is aggravated by maternal hypercholesterolemia and thus sets the basis for vascular disease later in life [30] .…”

Disease Stage-Dependent Accumulation of Lipid and Protein Oxidation Products in Human Atherosclerosis

“…Indeed, one study of human fetal fatty streak lesions reported the presence of malondialdehyde-and 4-hydroxynonenal-modified lysine (measured indirectly by immunological techniques) in the absence of monocytes/macrophages. 47 These authors suggested that intimal LDL accumulation and oxidation is an early event that contributes to monocyte recruitment into the vessel wall. To more precisely implicate a causal role of lipid (per)oxidation in atherogenesis the metabolism and/or removal of oxidation products is worthy of further study.…”

Does Therapeutic Intervention Achieve Slowing of Progression or Bona Fide Regression of Atherosclerotic Lesions?

“…43 More recently, these findings were extended to human fetuses, and a correlation was found with maternal hypercholesterolemia during pregnancy. 44 In addition, determination of the lesion area in the aortic arch revealed that the largest lesion per section was found in children up to 3 years of age and was significantly smaller than that in fetuses aged 6 months. 45 These results supported the notion that fatty streaks may already regress during late pregnancy.…”