Abstract 042: Evidence of Angiotensin II (AngII)-dependent Obesity-induced Hypertension in Female Mice Exposed to Postnatal Neglect

Abstract

Previously, we have shown that female mice subjected to maternal separation with early weaning (MSEW), a model of postnatal neglect, display exacerbated diet-induced obesity and high blood pressure (BP) compared with control mice. Female MSEW mice show activated renin-angiotensin system components, including increased plasma renin activity and adipose tissue-derived angiotensinogen secretion. The goal of this study was to test whether augmented obesity-induced hypertension in female MSEW mice is AngII-dependent. Mouse MSEW was achieved by repeated, daily separations from the dam and 4-day early weaning. Normally reared controls (C) were weaned at postnatal day 21. Each experimental group of female weanlings was comprised of 6 mice each and derived from 3 different litters, that were placed on high fat diet (HFD, 60% kcal from fat). After 18 weeks, mice were implanted with radiotelemetry for BP measurement. At week 20, average 24-hr systolic blood pressure (SBP) was 134±2 mmHg in MSEW mice and 126±2 in C (P<0.05). No significant changes in mean arterial pressure, diastolic blood pressure or heart rate were observed between groups. Next, we also determined the BP sensitivity to the acute administration of AngII (1, 10 and 50 ug/kg, s.c.). AngII-induced BP changes, assessed by BP area under the curve, were similar between MSEW and C mice at all doses (50 ug/kg dose:145±10 vs. 132±15 mmHgx30 min, respectively). Chronic enalapril treatment (2.5 mg/kg/day, drinking water, 7 days) was conducted to block endogenous AngII synthesis. Enalapril reduced SBP 15±2 mmHg in MSEW mice but only 6±1 mmHg in C mice (p<0.05). The BP response to acute AngII doses increased similarly in MSEW and C enalapril-treated mice, (50 ug/kg dose: 200±13 vs. 207±22 mmHgx30 min, respectively). In addition, BP and HR responses to acute injections (i.p) of mecamylamine (5 mg/kg), propranolol (5 mg/kg) or atropine (1 mg/kg) were similar between untreated MSEW and C mice, suggesting that exacerbated BP in female MSEW mice is independent of sympathetic or parasympathetic dysfunction. Taken together, these data provide evidence that increased BP in female MSEW mice results from elevated circulating AngII rather than enhanced AngII sensitivity or sympathetic nerve activity.