Hypercholesterolemia in pregnant mice does not affect atherosclerosis in adult offspring


      In humans, maternal hypercholesterolemia during pregnancy promotes microscopical fatty streaks in the children. The mechanism is unknown. Fatty streaks are clinically silent, and many of them regress and never develop into advanced atherosclerosis. The aim of this study was to investigate whether hypercholesterolemia in pregnant mice induced more advanced atherosclerosis in their adult progeny. Hypercholesterolemic (HC) apolipoprotein E knockout (apoE−/−) female mice were mated with normocholesterolemic (NC) wild-type (apoE+/+) males and vice versa. All parents were almost identical genetically except for apoE. Therefore, all progeny became genetically identical and heterozygous apoE+/−. They were born of either HC (i.e. apoE−/−) or NC (i.e. apoE+/+) mothers. The progeny were killed 6 months after birth and the amount of atherosclerosis in the aortic root was assessed. Females developed more atherosclerosis than males (P<0.001) but, regardless of sex, maternal hypercholesterolemia during pregnancy had no influence on the amount of atherosclerosis in adult progeny. Males of HC mothers had lower plasma cholesterol levels than males of NC mothers. Thus, in mice, maternal hypercholesterolemia during pregnancy does not promote the development of advanced atherosclerosis in their adult progeny.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Napoli C.
        • D'Armiento F.P.
        • Mancini F.P.
        • et al.
        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.
        J. Clin. Invest. 1997; 100: 2680-2690
        • Palinski W.
        • Napoli C.
        Pathophysiological events during pregnancy influence the development of atherosclerosis in humans.
        Trends Cardiovasc. Med. 1999; 9: 205-214
        • Napoli C.
        • Glass C.K.
        • Witztum J.L.
        • Deutsch R.
        • D'Armiento F.P.
        • Palinski W.
        Influence of maternal hypercholesterolemia during pregnancy on progression of early atherosclerotic lesions in childhood: fate of early lesions in children (FELIC) study.
        Lancet. 1999; 354 (see comments): 1234-1241
        • Stary H.C.
        • Chandler A.B.
        • Glagov S.
        • et al.
        A definition of initial, fatty streak, and intermediate lesions of atherosclerosis: a report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association.
        Circulation. 1994; 89: 2462-2478
        • Stary H.C.
        Natural history and histological classification of atherosclerotic lesions: an update.
        Arterioscler. Thromb. Vasc. Biol. 2000; 20: 1177-1178
        • Stary H.C.
        Lipid and macrophage accumulations in arteries of children and the development of atherosclerosis.
        Am. J. Clin. Nutr. 2000; 72: 1297S-1306S
        • Grundy S.M.
        • Pasternak R.
        • Greenland P.
        • Smith S.
        • Fuster V.
        Assessment of cardiovascular risk by use of multiple-risk-factor assessment equations: a statement for healthcare professionals from the American Heart Association and the American College of Cardiology.
        Circulation. 1999; 100: 1481-1492
        • Zhang S.H.
        • Reddick R.L.
        • Burkey B.
        • Maeda N.
        Diet-induced atherosclerosis in mice heterozygous and homozygous for apolipoprotein E gene disruption.
        J. Clin. Invest. 1994; 94: 937-945
        • van Ree J.H.
        • van den Broek W.J.
        • Dahlmans V.E.
        • et al.
        Diet-induced hypercholesterolemia and atherosclerosis in heterozygous apolipoprotein E-deficient mice.
        Atherosclerosis. 1994; 111: 25-37
        • Piedrahita J.A.
        • Zhang S.H.
        • Hagaman J.R.
        • Oliver P.M.
        • Maeda N.
        Generation of mice carrying a mutant apolipoprotein E gene inactivated by gene targeting in embryonic stem cells.
        Proc. Natl. Acad. Sci. USA. 1992; 89: 4471-4475
        • Paigen B.
        • Morrow A.
        • Holmes P.A.
        • Mitchell D.
        • Williams R.A.
        Quantitative assessment of atherosclerotic lesions in mice.
        Atherosclerosis. 1987; 68: 231-240
        • Nicoletti A.
        • Kaveri S.
        • Caligiuri G.
        • Bariety J.
        • Hansson G.K.
        Immunoglobulin treatment reduces atherosclerosis in apo E knockout mice.
        J. Clin. Invest. 1998; 102: 910-918
        • Bentzon J.F.
        • Skovenborg E.
        • Hansen C.
        • et al.
        Red wine does not reduce mature atherosclerosis in apolipoprotein E-deficient mice.
        Circulation. 2001; 103: 1681-1687
        • Napoli C.
        • de Nigris F.
        • Welch J.S.
        • et al.
        Maternal hypercholesterolemia during pregnancy promotes early atherogenesis in LDL receptor-deficient mice and alters aortic gene expression determined by microarray.
        Circulation. 2002; 105: 1360-1367
        • Napoli C.
        • Witztum J.L.
        • Calara F.
        • de Nigris F.
        • Palinski W.
        Maternal hypercholesterolemia enhances atherogenesis in normocholesterolemic rabbits, which is inhibited by antioxidant or lipid-lowering intervention during pregnancy: an experimental model of atherogenic mechanisms in human fetuses.
        Circ. Res. 2000; 87 (in process citation): 946-952
        • Norman J.F.
        • LeVeen R.F.
        Maternal atherogenic diet in swine is protective against early atherosclerosis development in offspring consuming an atherogenic diet postnatally.
        Atherosclerosis. 2001; 157: 41-47
        • McGill Jr., H.C.
        • McMahan C.A.
        • Herderick E.E.
        • Malcom G.T.
        • Tracy R.E.
        • Strong J.P.
        Origin of atherosclerosis in childhood and adolescence.
        Am. J. Clin. Nutr. 2000; 72: 1307S-1315S
        • Berenson G.S.
        • Srinivasan S.R.
        • Bao W.
        • Newman W.P.
        • Tracy R.E.
        • Wattigney W.A.
        Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa Heart Study.
        N. Engl. J. Med. 1998; 338: 1650-1656
        • McGill H.C.
        Nutrition in early life and cardiovascular disease.
        Curr. Opin. Lipidol. 1998; 9: 23-27
        • Virmani R.
        • Kolodgie F.D.
        • Burke A.P.
        • Farb A.
        • Schwartz S.M.
        Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions.
        Arterioscler. Thromb. Vasc. Biol. 2000; 20: 1262-1275
        • McGill Jr., H.C.
        Fatty streaks in the coronary arteries and aorta.
        Lab. Invest. 1968; 18: 560-564
        • Knowles J.W.
        • Maeda N.
        Genetic modifiers of atherosclerosis in mice.
        Arterioscler. Thromb. Vasc. Biol. 2000; 20: 2336-2345
        • Ravn H.B.
        • Korsholm T.L.
        • Falk E.
        Oral magnesium supplementation induces favorable antiatherogenic changes in apoE-deficient mice.
        Arterioscler. Thromb. Vasc. Biol. 2001; 21: 858-862
        • Hofker M.H.
        • van Vlijmen B.J.
        • Havekes L.M.
        Transgenic mouse models to study the role of apoE in hyperlipidemia and atherosclerosis.
        Atherosclerosis. 1998; 137: 1-11
        • Caligiuri G.
        • Nicoletti A.
        • Zhou X.
        • Tornberg I.
        • Hansson G.K.
        Effects of sex and age on atherosclerosis and autoimmunity in apoE-deficient mice.
        Atherosclerosis. 1999; 145: 301-308
        • Jollie W.P.
        Development, morphology, and function of the yolk-sac placenta of laboratory rodents.
        Teratology. 1990; 41: 361-381
        • Woollett L.A.
        The origins and roles of cholesterol and fatty acids in the fetus.
        Curr. Opin. Lipidol. 2001; 12: 305-312
        • Neary R.H.
        • Kilby M.D.
        • Kumpatula P.
        • et al.
        Fetal and maternal lipoprotein metabolism in human pregnancy.
        Clin. Sci. (Colch). 1995; 88: 311-318
        • Mazurkiewicz J.C.
        • Watts G.F.
        • Warburton F.G.
        • Slavin B.M.
        • Lowy C.
        • Koukkou E.
        Serum lipids, lipoproteins and apolipoproteins in pregnant non-diabetic patients.
        J. Clin. Pathol. 1994; 47: 728-731
        • Martin U.
        • Davies C.
        • Hayavi S.
        • Hartland A.
        • Dunne F.
        Is normal pregnancy atherogenic?.
        Clin. Sci. (Colch). 1999; 96: 421-425
        • Martin D.E.
        • Wolf R.C.
        • Meyer R.K.
        Plasma lipid levels during pregnancy in the rhesus monkey (Macaca mulatta).
        Proc. Soc. Exp. Biol. Med. 1971; 138: 638-641
        • Belknap W.M.
        • Dietschy J.M.
        Sterol synthesis and low-density lipoprotein clearance in vivo in the pregnant rat, placenta, and fetus. Sources for tissue cholesterol during fetal development.
        J. Clin. Invest. 1988; 82: 2077-2085
        • Munilla M.A.
        • Herrera E.
        A cholesterol-rich diet causes a greater hypercholesterolemic response in pregnant than in non-pregnant rats and does not modify fetal lipoprotein profile.
        J. Nutr. 1997; 127: 2239-2245
        • Jurevics H.A.
        • Kidwai F.Z.
        • Morell P.
        Sources of cholesterol during development of the rat fetus and fetal organs.
        J. Lipid Res. 1997; 38: 723-733
        • Parker C.R.
        • Deahl T.
        • Drewry P.
        • Hankins G.
        Analysis of the potential for transfer of lipoprotein-cholesterol across the human placenta.
        Early Hum. Dev. 1983; 8: 289-295
        • Wyne K.L.
        • Woollett L.A.
        Transport of maternal LDL and HDL to the fetal membranes and placenta of the Golden Syrian hamster is mediated by receptor-dependent and receptor-independent processes.
        J. Lipid Res. 1998; 39: 518-530
        • Woollett L.A.
        Fetal lipid metabolism.
        Front. Biosci. 2001; 6: D536-D545
        • Farese R.V.
        • Cases S.
        • Ruland S.L.
        • et al.
        A novel function for apolipoprotein B: lipoprotein synthesis in the yolk sac is critical for maternal–fetal lipid transport in mice.
        J. Lipid Res. 1996; 37: 347-360
        • Barker D.J.
        Mothers, Babies and Health in Later Life. Churchill Livingstone, New York1998
        • Waterland R.A.
        • Garza C.
        Potential mechanisms of metabolic imprinting that lead to chronic disease.
        Am. J. Clin. Nutr. 1999; 69 (see comments): 179-197
        • Petry C.J.
        • Ozanne S.E.
        • Hales C.N.
        Programming of intermediary metabolism.
        Mol. Cell. Endocrinol. 2001; 185: 81-91
        • Breslow J.L.
        • Plump A.S.
        • Dammerman M.
        New mouse models of lipoprotein disorders and atherosclerosis.
        in: Fuster V. Ross R. Topol E.J. Atherosclerosis and Coronary Disease. Lippincott/Raven, New York1996: 363-378