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

Claudio Napoli, Francesco Paolo D'Armiento, Francesco Paolo Mancini, Alfredo Postiglione, Joseph L. Witztum, Giuseppe Palumbo, Wulf Palinski

Research output: Contribution to journalArticle

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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 ± 1.3 mo). For this purpose, a systematic assessment of fatty streak formation was carried out in fetal aortas from mocholesterolemic mothers (n = 22), hypercholesterolemic mothers (n = 33), and mothers who were hypercholesterolemic only during pregnancy (n = 27). Fetal plasma cholesterol levels showed a strong inverse correlation with fetal age (R = -0.88, P <0.0001). In fetuses younger than 6 mo, fetal plasma cholesterol levels correlated with maternal ones (R = 0.86, P = 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 ± 87,449 and 451,255 ± 37,448 μm2 per section, respectively; mean ± SD) than aortas from normocholesterolemic mothers (61,862 ± 9,555 μm2; P <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 OxLDL 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.

Original languageEnglish
Pages (from-to)2680-2690
Number of pages11
JournalJournal of Clinical Investigation
Volume100
Issue number11
Publication statusPublished - Dec 1 1997

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Tunica Intima
Hypercholesterolemia
LDL Lipoproteins
Aorta
Monocytes
Mothers
Macrophages
Thoracic Aorta
Gestational Age
Epitopes
Atherosclerosis
Fetus
oxidized low density lipoprotein
Cholesterol
Foam Cells
Abdominal Aorta
Apolipoproteins B
Spontaneous Abortion
Fetal Development
Malondialdehyde

Keywords

  • Arteriosclerosis
  • Fetal development
  • Hypercholesterolemia
  • Lipoprotein oxidation
  • Macrophages

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Fatty streak formation occurs in human fetal aortas and is greatly enhanced maternal, hypercholesterolemia. Intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atheroeclerotic lesions. / Napoli, Claudio; D'Armiento, Francesco Paolo; Mancini, Francesco Paolo; Postiglione, Alfredo; Witztum, Joseph L.; Palumbo, Giuseppe; Palinski, Wulf.

In: Journal of Clinical Investigation, Vol. 100, No. 11, 01.12.1997, p. 2680-2690.

Research output: Contribution to journalArticle

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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 ± 1.3 mo). For this purpose, a systematic assessment of fatty streak formation was carried out in fetal aortas from mocholesterolemic mothers (n = 22), hypercholesterolemic mothers (n = 33), and mothers who were hypercholesterolemic only during pregnancy (n = 27). Fetal plasma cholesterol levels showed a strong inverse correlation with fetal age (R = -0.88, P <0.0001). In fetuses younger than 6 mo, fetal plasma cholesterol levels correlated with maternal ones (R = 0.86, P = 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 ± 87,449 and 451,255 ± 37,448 μm2 per section, respectively; mean ± SD) than aortas from normocholesterolemic mothers (61,862 ± 9,555 μm2; P <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 OxLDL 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.",
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T1 - Fatty streak formation occurs in human fetal aortas and is greatly enhanced maternal, hypercholesterolemia. Intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atheroeclerotic lesions

AU - Napoli, Claudio

AU - D'Armiento, Francesco Paolo

AU - Mancini, Francesco Paolo

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AU - Witztum, Joseph L.

AU - Palumbo, Giuseppe

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N2 - 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 ± 1.3 mo). For this purpose, a systematic assessment of fatty streak formation was carried out in fetal aortas from mocholesterolemic mothers (n = 22), hypercholesterolemic mothers (n = 33), and mothers who were hypercholesterolemic only during pregnancy (n = 27). Fetal plasma cholesterol levels showed a strong inverse correlation with fetal age (R = -0.88, P <0.0001). In fetuses younger than 6 mo, fetal plasma cholesterol levels correlated with maternal ones (R = 0.86, P = 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 ± 87,449 and 451,255 ± 37,448 μm2 per section, respectively; mean ± SD) than aortas from normocholesterolemic mothers (61,862 ± 9,555 μm2; P <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 OxLDL 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.

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