(915) Maternal Hyperleptinemia Induces Sex-Specific Hypertension in Male Mice Offspring

Objective:
Elevated leptin levels in pregnancy is associated with preeclampsia, hypertension and adverse fetal outcomes such as low birth weight. In a novel animal model, our laboratory demonstrated that elevating leptin levels in pregnant mice induces maternal hypertension, vascular endothelial dysfunction and decreases offspring weight. However, whether hyperleptinemia of pregnancy induces long-term adverse cardiovascular outcomes in offspring is unknown. We hypothesized that leptin infusion in pregnant mice in mid-late gestation induces hypertension in adult offspring.

Study Design:
We administered mouse recombinant leptin (LEP, 0.9 mg/kg/day) or saline (XLEP) via subcutaneous mini-osmotic infusion pumps from gestation day 11 to end of gestation. Offspring were weaned and aged to 6 months, and one female and one male mouse utilized from each litter for blood pressure (BP) measurement. Offspring were implanted with radiotelemeters for conscious BP. After 7 days of baseline on normal salt diet (NSD), mice were transitioned to 4% high salt diet (HSD) for 7 days, followed by HSD + angiotensin II (ANG II, 490 ng/kg/min) for 7 days. Groups included are XLEP+NSD, XLEP+HSD, XLEP+HSD+ANG II, LEP+NSD, LEP+HSD, and LEP+HSD+ANG II for both sexes.

Results:
At baseline and HSD only conditions, leptin did not produce an effect on BP or HR in offspring. Interestingly, in Ang-II+HSD, only LEP males showed significant elevation in blood pressure compared to XLEP male offspring (Mean ± SEM; 133±3.9 vs. 101±8.4 respectively, p=0.003), with no difference among the LEP female offspring compared to XLEP females (Mean ± SEM; 124.6±8 vs. 122.4±4.9, respectively, p >0.05)

Conclusion:
Leptin-induced preeclampsia in mice causes male-specific in-utero programming, resulting in increased Ang-II sensitivity to hypertensive stimuli - a novel demonstration of sex-specific fetal cardiovascular programming.