Angiotensin II Type 1 Receptor Agonistic Autoantibody Blockade Improves Postpartum Hypertension and Cardiac Mitochondrial Function in Rat Model of Preeclampsia

Abstract

Women with preeclampsia (PE) have a greater risk of developing hypertension, cardiovascular disease (CVD), and renal disease later in life. Angiotensin II type I receptor agonistic autoantibodies (AT1-AAs) are elevated in women with PE during pregnancy and up to 2 years postpartum (PP), and in the reduced uterine perfusion pressure (RUPP) rat model of PE. Blockade of AT1-AA with a specific 7 amino acid peptide binding sequence (‘n7AAc’) improves pathophysiology observed in RUPP rats; however, the long-term effects of AT1-AA inhibition in PP is unknown. Pregnant Sprague Dawley rats were divided into 3 groups: normal pregnant (NP) (n = 16), RUPP (n = 15), and RUPP+‘n7AAc’ (n = 16). Gestational day 14, RUPP surgery was performed and ‘n7AAc’ (144 µg/day) administered via osmotic minipump. At 10 weeks PP, mean arterial pressure (MAP), renal glomerular filtration rate (GFR) and cardiac functions, and cardiac mitochondria function were assessed. MAP was elevated PP in RUPP vs NP (126 ± 4 vs. 116 ± 3 mmHg, p < 0.05), but was normalized in in RUPP+‘n7AAc’ (109 ± 3 mmHg) vs. RUPP (p < 0.05). PP heart size was reduced by RUPP+’n7AAc’ vs. RUPP rats (p < 0.05). Complex IV protein abundance and enzymatic activity, along with glutamate/malate-driven respiration (complexes I, III, and IV), were reduced in the heart of RUPP vs NP rats which was prevented with ‘n7AAc’. AT1-AA inhibition during pregnancy not only improves blood pressure and pathophysiology of PE in rats during pregnancy, but also long-term changes in blood pressure, cardiac hypertrophy, and cardiac mitochondrial function PP.

AT1-AA Infusion during Pregnancy Impairs CBF Autoregulation Postpartum

“…Importantly, we show that infusion of AT1-AA to levels to mimic that seen in previously PE women causes hypertension and impaired CBF postpartum. Studies that have investigated the postpartum period following PE have focused on whether there are prolonged effects on blood pressure or cardiac function [25][26][27], but to our knowledge, this is one of the first studies to examine factors that may be responsible for cerebrovascular dysfunction postpartum for PE women.…”

“…Circulating AT1-AA levels are known to be elevated for up to 8 years postpartum following a PE pregnancy [24] however, the cerebrovascular consequences of this sustained presence are unknown. AT1-AA exposure during pregnancy increases susceptibility to ischemic injury and other cardiovascular morbidities in the heart postpartum [25][26][27]. Previous studies in animal models of PE found that autoregulation of CBF is impaired during pregnancy [9,28,29].…”

“…Angiotensin II receptor blockers have attenuated impaired CBF autoregulation in the reduced uterine perfusion pressure (RUPP) model of PE implicating the AT1 receptor and its agonists including AT1-AA [9]. Additionally, a 'n7AAc' peptide, which blocks the actions of AT1-AA, improves postpartum cardiac outcomes in the RUPP model [27] and also improves CBF autoregulation in the RUPP model during pregnancy [29]. Taken together, these studies implicate AT1-AA during pregnancy and in postpartum impairment of CBF.…”