Gestational hypertension increases risk of seizures in children and mice

Abstract

Gestational hypertension (GH) is prevalent, with life-long health burdens for mothers and their children exposed in utero. We analyzed the nation-wide Epic Cosmos dataset and found significantly higher rates of seizures in children of mothers with GH than in children of normotensive mothers. Complementary studies of nested Iowa and Stanford cohorts and a large Taiwanese cohort also revealed significantly increased seizure risk after covariate adjustments. We modeled this association in an angiotensin (ANG) II mouse model of GH. Maternal ANG II significantly increased seizure grade and deaths elicited by pilocarpine among male but not female offspring. Electrical stimulation increased seizure grade and death across sexes in offspring from ANG II-treated dams. Proinflammatory and microglial gene expression in the brain were upregulated only in male offspring from ANG II-treated dams. Chronic phenylephrine, a GH model lacking the maternal proinflammatory aspects of ANG II, induced similar offspring seizure phenotypes. PLX5622-induced depletion of microglia or antiinflammatory pentoxifylline abolished this sensitized seizure response and lowered mortality in the ANG II model. These results suggest that GH programs offspring risk for seizures in a sex-dependent manner in humans and mice. Neuroinflammatory mechanisms may contribute to the elevated sensitivity and mortality from seizures elicited by GH exposure in utero.

Keywords: Hypertension; Inflammation; Neuroscience; Seizures.

Figure 1. Maternal ANG II– or PE-induced GH and their effects on the neonates.

Changes in MAP (A) and HR (B) in mouse dams with chronic infusion of saline, ANG II, or PE during pregnancy. (C and D) Litter size and birth weights. Two-way ANOVA; *P < 0.05 vs. saline dams; ^#P < 0.05 vs. PE-treated dams; ^†P < 0.05 vs. pups of saline-treated dams. Data are shown as the mean ± SEM.

Figure 2. Hippocampal pro-inflammation with prenatal ANG II or PE and modulation by PTX or PLX5622.

Quantitative comparison of the mRNA expression of proinflammatory cytokines (Tnf) and a microglial marker (Cd11b) in the hippocampus of adult offspring (10 weeks old) from normotensive (saline-treated) dams and from dams with ANG II–induced hypertension (male offspring, A and female offspring, B) or PE-induced hypertension (offspring of both sexes, C) (n = 5–6/group). One-way ANOVA; *P < 0.05 vs. male offspring of saline-treated dams; ^†P < 0.05 vs. control ANG II offspring; ^‡P < 0.05 vs. other 3 groups of offspring. Data are shown as the mean ± SEM.

Figure 3. Seizure induction in offspring from ANG II–treated dams.

Increased sensitivity and mortality to pilocarpine-induced (A and B) or ES-induced (C and D) seizures in adult male and female offspring of dams with ANG II–induced hypertension when compared with offspring of normotensive (saline-treated) dams. Sex differences in the sensitivity and mortality induced by pilocarpine were noted (n = 7–10/group). Two-way ANOVA followed by Tukey’s test; *P < 0.05 vs. male offspring of saline-treated dams; ^#P < 0.05 vs. female offspring of saline-treated dams; ^¥P < 0.05 vs. female offspring of ANG II–treated dams. Data are shown as the mean ± SEM.

Figure 4. Seizure induction in offspring from PE–treated dams.

Increased sensitivity and mortality to pilocarpine-induced (A and B) or ES-induced (C and D) seizures in adult male and female offspring of dams with PE–induced hypertension when compared with offspring of normotensive (saline-treated) dams. There were sex differences in the sensitivity and mortality induced by pilocarpine (n = 7–10/group). Two-way ANOVA followed by Tukey’s test; *P < 0.05 vs. male offspring of saline-treated dams; ^#P < 0.05 vs. female offspring of saline-treated dams; ^¥P < 0.05 vs. female offspring of PE-treated dams. Data are shown as the mean ± SEM.

Figure 5. PTX rescue of male offspring seizure phenotypes.

Pretreatment with PTX significantly attenuated seizure responses and prevented mortality after pilocarpine (A and B) or ES (C and D) treatment in adult male offspring of dams with ANG II–induced hypertension (n = 8–10/group). Two-way ANOVA followed by Tukey’s test; *P < 0.05 vs. male offspring of saline-treated dams; ^†P < 0.05 vs. male offspring with PTX treatment. Data are shown as the mean ± SEM.

Figure 6. PTX rescue of female offspring seizure phenotypes.

Pretreatment with PTX significantly reduced seizure responses and mortality after pilocarpine (A) or ES (B and C) treatment in adult female offspring of both normotensive (saline-treated) dams and dams with ANG II–induced hypertension (n = 7–9/group). Two-way ANOVA followed by Tukey’s test; ^#P < 0.05 vs. female offspring of saline-treated dams; ^‡P < 0.05 vs. PTX-treated female offspring. Data are shown as the mean ± SEM.

Figure 7. PLX5622 rescue of male offspring seizure phenotypes.

Pretreatment with PLX5622 significantly attenuated seizure responses and abolished mortality after pilocarpine (A and B) or ES (C and D) treatment in adult male offspring of dams with ANG II–induced hypertension (n = 8–11/group). Two-way ANOVA followed by Tukey’s test; *P < 0.05 vs. male offspring of saline-treated dams; ^†P < 0.05 vs. male offspring with PLX 5622 treatment. Data are shown as the mean ± SEM.

Figure 8. PLX5622 rescue of female offspring seizure phenotypes.

Pretreatment with PLX5622 significantly reduced seizure responses and mortality after pilocarpine (A) or ES (B and C) treatment in adult female offspring of dams with ANG II–induced hypertension (n = 7–9/group). Two-way ANOVA followed by Tukey’s test; ^#P < 0.05 vs. female offspring of saline-treated dams; ^‡P < 0.05 vs. female offspring with PLX 5622 treatment. Data are shown as the mean ± SEM.