Preeclampsia Model of Gestational Hyperleptinemia Shows Male-Specific Circadian Dysregulation and Increased Blood Pressure Variability

Preeclampsia (PE) is a hypertensive disorder of pregnancy imposing high cardiovascular disease risk during and after pregnancy on both mother and offspring. We showed that leptin infusion at mid-to-end of gestation induces key PE features in mice: hypertension, fetal growth restriction, and endothelial dysfunction. High leptin levels are frequently associated with obesity in PE patients, therefore, the role for hyperleptinemia independent of obesity in long-term cardiovascular risk conferred by PE is unknown. We sought to test the hypothesis that offspring born to hyperleptinemic lean dams during pregnancy are at higher susceptibility to hypertension later in life. C57BL/6J females were bred for timed pregnancy (12-14 wk old). On gestational day 11, dams were implanted with osmotic pumps with saline (XLEP) or leptin (LEP; 0.9mg/kg/day). Offspring were weaned at 21 d. At 3 mo. age, 1 male and 1 female randomly selected from each litter were implanted with telemetry probes and baseline blood pressure (BP) recording initiated for one week after recovery. Mice were shifted to 4% high salt diet (HSD) for 1 wk and angiotensin II pump (Ang-II, 490 ng/kg/min) for 2 wk, resulting in 6 groups: XLEP+NSD, XLEP+HSD, XLEP+HSD+Ang-II, LEP+NSD, LEP+HSD, LEP+HSD+Ang-II (n=6M, 6F/group). BP circadian rhythm was assessed by calculating the mean BP difference between active and resting phases in LEP and XLEP mice. For BP variability, we performed average real variability (ARV) analysis index using absolute BP values extracted every 15 min and averaged for the hour. At the end of protocol, mice were euthanized and kidneys were collected for RNA isolation and qPCR. 1W-ANOVA with Tukey’s post hoc test and student t test were used for BP data and gene expression, respectively. Our data show that at baseline, LEP mice have no BP differences compared to XLEP. However, LEP+HSD+Ang-II M showed an elevation in BP compared to XLEP+HSD+Ang-II M offspring (Mean±SEM; 133±3.9 vs. 101±8.4 mean arterial pressure, respectively, p=0.003). Our data showed that only in LEP+HSD+Ang-II males was an increased ARV compared to XLEP+HSD+Ang-II male (area under curve; Ang-II; 104±8 vs.85.14±5.5, respectively; p=0.03). Furthermore, we observed blunting in the MAP circadian rhythm of LEP male offspring compared to XLEP males at the baseline BP recording (ΔMAP; 7.9±0.5 vs.14.2±0.5, respectively; p< 0.0001). This was associated with increased kidney Bmal1 gene expression in LEP M compared to XLEP M (Bmal1/18S Fold change to XLEP M: 4.4±1.3, p=0.007). Interestingly, LEP female mice showed no difference from XLEP females for the mean BP readings, BP dipping, ARV, or Bmal1 expression (p >0.05). We conclude that gestational hyperleptinemia induces male-specific programming that increases the susceptibility to hypertension and BP variability, potentially attributable to circadian rhythm dysregulation. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.