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-Ldlr^tm1Her/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.