P304	The effect of maternal hypercholesterolemia on vascular development and fetal plasma lipid levels.
1F.Alkemade, 1M.DeRuiter, 2K.Willems van Dijk, 1C.VanMunsteren, 3L.Havekes, 1A.Gittenberger-de Groot
1Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, NL; 2Department of Human Genetics, Leiden University Medical Center, Leiden, NL; 3TNO-Quality of life, Gaubius Laboratory, Leiden, NL.

Intrauterine exposure of the human fetus to high levels of cholesterol appears to lead to increased formation of fatty streaks in the fetal aorta and promotes development of atherosclerosis in adult life. However, little is known on the contribution of genetic background of the fetus on intrinsic lipid metabolism and vascular remodeling in combination with maternal normo- or hypercholesterolemia (NC, HC respectively). We hypothesize that maternal HC results in changes in fetal plasma lipid levels leading to altered vascular remodeling in the embryo and increased susceptibility to vascular disease in adult offspring. To study the intrauterine effect of fetal genetic background the LDL receptor and apoE knockout mouse strains were used. Crossbreeding with wild type C57Bl/6Jico (wt) was performed to generate: wt fetuses in wt mothers, heterozygous fetuses in wt mothers and heterozygous fetuses in knockout mothers. Fasted plasma cholesterol and triglyceride levels of the mice were quantified enzymatically before pregnancy and at the moment of harvesting the fetuses (day 17.5). Fetuses were dissected and blood samples were obtained through decapitation. Results of apoE crossbreeding experiments show no significant differences in plasma cholesterol and triglyceride levels between wt and heterozygous fetuses developing under maternal NC. HC of the mother on the other hand significantly increases the plasma cholesterol level in apoE heterozygous fetuses (1.5 vs 2.3 mmol/l, p=0.000). Plasma triglyceride levels are low in all fetuses (0.4 mmol/l). A significant increase however is observed between plasma triglyceride levels of wt mothers carrying wt and apoE heterozygous fetuses (1.0 vs 1.6 mmol/l, p=0.01). It is concluded that at day 17.5 fetal plasma cholesterol level is related to maternal cholesterol status. A HC environment increases the intrinsic cholesterol level of fetuses possibly resulting in enhanced oxidative stress during embryonic development and disturbance of vascular remodeling. The differences in maternal plasma triglyceride levels suggest that fatty acid metabolism status is not independent of fetal genotype. Perivascular cuff placement will be used to study the effect of intra-uterine HC exposure on the susceptibility to develop atherosclerosis in adult life. This research was supported by a grant from the Netherlands Heart Foundation NHF2003B241.

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