76: The role of LOX-1 receptor in sex-specific altered fetal programming of cardiovascular function in a preeclampsia-like murine model

Abstract

Adult male mice exposed to preeclampsia in utero develop elevated blood pressure (BP) and decreased endothelium dependent relaxation compared to controls, most evident at 6 months of age, while female offspring do not. We previously showed that prenatal pravastatin prevented these changes. Lectin-like oxidized low density lipoprotein receptor 1 (LOX-1) is an endothelial cell receptor that is upregulated under inflammatory and oxidative conditions, and is associated with hypertension. Our objective was to evaluate the role of LOX-1 in these gender-specific phenotypic changes, and its response to prenatal pravastatin treatment, using a well-established animal model of preeclampsia. CD-1 mice were injected with Adv-sFlt-1 and randomly allocated to pravastatin (sFlt-prav) or water (sFlt) until weaning. A control group was injected with adenovirus carrying the murine immunoglobulin G2α Fc fragment (mFc). Offspring were sacrificed at 3 and 6 months. RNA was extracted from the aorta, and mRNA expression of LOX-1 was measured using quantitative RT-PCR. Statistical analysis was performed using ANOVA and Student t tests. There were no differences in LOX-1 mRNA expression between groups or gender at 3 months. At 6 months, LOX-1 mRNA in sFlt offspring was upregulated by more than 2 folds compared to mFc controls (p=0.01). Prenatal pravastatin reduced the mRNA to a level not significantly different from either sFlt-1 or control (Figure). In addition, at 6 months male offspring had significantly higher LOX-1 mRNA compared with females (6.25±0.87 vs 3.19±0.36, p=0.01). Increased expression of LOX-1 parallels the temporal and gender-specific changes in adult cardiovascular function observed in this animal model of fetal programming. These findings support a role for LOX-1 in the fetal programming of adult diseases induced by preeclampsia, and of its involvement, at least partially, in the beneficial effects of maternal treatment with pravastatin.