In utero programming of adult vascular function in transgenic mice lacking low-density lipoprotein receptor

Objective The objective of this study was to examine the role of maternal hypercholesterolemia in fetal programming of adult vascular function using transgenic mice lacking the low-density lipoprotein receptor (LDLR). Study Design Homozygous LDLR knockout mice (B6.129S7- Ldlrtm1Her /J, LDLR-/-KO ) and their wild-type controls (C57BL/6J, LDLR+/+WT ) were cross-bred to produce 4 litter groups: LDLR-/-KO , maternally derived heterozygous (LDLR±Mat ), paternally derived heterozygous (LDLR±Pat ) and LDLR+/+WT . Female and male offspring were killed at 10-12 weeks of age, and carotid arteries were used for in vitro experiments. Results The dose responses to phenylephrine were significantly higher in LDLR-/-KO and LDLR±Mat male offspring. The contractile responses to phenylephrine in female mice were significantly increased only in the LDLR-/-KO offspring. Maximal Ca2+ contraction was higher in LDLR-/-KO male and female offspring. Conclusion Despite being genomically similar, heterozygous offspring that developed in a hypercholesterolemic maternal environment had abnormal vascular responses later in life compared with those that developed in a normal environment.