Female Mice Exposed to Postnatal Neglect Display Angiotensin II-Dependent Obesity-Induced Hypertension

Abstract

Background We have previously reported that female mice exposed to maternal separation and early weaning (MSEW), a model of early life stress, show exacerbated diet-induced obesity associated with hypertension. The goal of this study was to test whether MSEW promotes angiotensin II-dependent hypertension via activation of the renin-angiotensin system in adipose tissue. Methods and Results MSEW was achieved by daily separations from the dam and weaning at postnatal day 17, while normally reared controls were weaned at postnatal day 21. Female controls and MSEW weanlings were placed on a low-fat diet (LF, 10% kcal from fat) or high-fat diet (HF, 60% kcal from fat) for 20 weeks. MSEW did not change mean arterial pressure in LF-fed mice but increased it in HF-fed mice compared with controls (P<0.05). In MSEW mice fed a HF, angiotensin II concentration in plasma and adipose tissue was elevated compared with controls (P<0.05). In addition, angiotensinogen concentration was increased solely in adipose tissue from MSEW mice (P<0.05), while angiotensin-converting enzyme protein expression and activity were similar between groups. Chronic enalapril treatment (2.5 mg/kg per day, drinking water, 7 days) reduced mean arterial pressure in both groups of mice fed a HF (P<0.05) and abolished the differences due to MSEW. Acute angiotensin II-induced increases in mean arterial pressure (10 μg/kg SC) were attenuated in untreated MSEW HF-fed mice compared to controls (P<0.05); however, this response was similar between groups in enalapril-treated mice. Conclusions The upregulation of angiotensinogen and angiotensin II in adipose tissue could be an important mechanism by which female MSEW mice fed a HF develop hypertension.

Keywords: adipose tissue; hypertension; maternal separation; obesity; renin‐angiotensin system.

Figure 1

Effect of maternal separation and early weaning (MSEW) in plasma RAS components. A, Plasma angiotensinogen (ng/mL), (B) plasma renin concentration (PRC, ng/mL), and (C) angiotensin II concentration (ng/mL) in female control (white bars) and MSEW (black bars) mice fed a low‐fat diet (LF) or a high‐fat diet (HF). Data were analyzed by 2‐way ANOVA followed by Bonferroni post hoc test and reported as mean±SEM. *P<0.05 vs. control, ^# P<0.05 vs. LF; n=8 per group in HF‐fed mice.

Figure 2

RAS components in gonadal white adipose tissue (gWAT). A, Angiotensin II concentration (angiotensin II, ng angiotensin II/mg protein), (B) angiotensinogen levels in fat explant media (μg/g); and (C) angiotensinogen levels in gWAT explant tissue (ng/g) in female control (white bars) and maternal separation and early weaning (MSEW) (black bars) mice fed a low‐fat diet (LF) or a high‐fat diet (HF). Data were analyzed by 2‐way ANOVA followed by Bonferroni post hoc test and reported as mean±SEM. *P<0.05 vs. control, ^# P<0.05 vs. LF; (A) n=8 per group; (B) n=8 per group media explant; (C) n=6 per group tissue explant.

Figure 3

Effect of maternal separation and early weaning (MSEW) in angiotensin‐converting enzyme (ACE). A, expression (% control LF) and (B) activity (20 μg protein) in perigonadal white adipose tissue (gWAT) of female control (white bars) and MSEW (black bars) mice fed a low‐fat diet (LF) and high‐fat diet (HF); n=3 control LF, 8=control HF, 4=MSEW LF, 8=MSEW HF.

Figure 4

Effect of diet or angiotensin‐converting enzyme (ACE) inhibitor on blood pressure. Delta blood pressure changes from LF to HF in female control (white solid bars) and maternal separation and early weaning (MSEW) (black solid bars): (A) Mean arterial pressure (MAP, mm Hg); (B) Systolic blood pressure (SBP, mm Hg); (C) Diastolic blood pressure (DBP, mm Hg). Delta blood pressure changes from untreated to enalapril‐treated HF‐fed female control (white dotted bars) and MSEW (black dotted bars): (D) MAP; (E) SBP; (F) DBP. Data were analyzed by 1‐way ANOVA followed by Tukey's post hoc test and reported as mean±SEM.*P<0.05 vs. control; n=6 per group.

Figure 5

Effect of HF on acute angiotensin II–induced pressor response (10 ng/kg, SC) in female control (white bars) and maternal separation and early weaning (MSEW) (black bars) mice. A, Delta systolic blood pressure changes (delta SBP, mm Hg) in untreated (solid bars) and (B) enalapril‐treated (dotted bars). Data were analyzed by 2‐way ANOVA followed by Bonferroni post hoc test and reported as mean±SEM. *P<0.05 vs. control, ^# P<0.05 vs. LF, n=6 per group.