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  • Title: Inhibition of angiotensin II type 1 receptor agonistic autoantibodies by direct binding does not impact reduced uterine perfusion pressure offspring birthweight and blood pressure at adulthood.
    Author: Solise D, Campbell N, Ashraf U, Herrock O, Crudup B, Mallette J, Willis A, Rawls AZ, Turner T, Cockrell K, Zheng B, Deer E, Amaral L, Alexander BT, Lamarca B.
    Journal: Am J Obstet Gynecol MFM; 2023 Jun; 5(6):100945. PubMed ID: 36990181.
    Abstract:
    BACKGROUND: Preeclampsia, a new-onset hypertension with end-organ damage in pregnancy, is associated with maternal death and morbidity, low birthweight, and B cells producing agonistic autoantibodies to the angiotensin II type 1 receptor. Angiotensin II type 1 receptor agonistic autoantibodies are produced during pregnancy and after delivery and are in the fetal circulation of women with preeclampsia. Angiotensin II type 1 receptor agonistic autoantibodies are shown to contribute to endothelial dysfunction, renal dysfunction, hypertension, fetal growth restriction, and chronic inflammation in women with preeclampsia. The reduced uterine perfusion pressure rat model of preeclampsia exhibits these features. In addition, we have shown that the administration of a 'n7AAc', which blocks the actions of the angiotensin II type 1 receptor autoantibodies, improves preeclamptic features in the rat with reduced uterine perfusion pressure. However, the effect of a 'n7AAc' on the long-term health of the offspring of rats with reduced uterine perfusion pressure is unknown. OBJECTIVE: This study aimed to test the hypothesis that inhibition of angiotensin II type 1 receptor autoantibodies during pregnancy will improve offspring birthweight and prevent increased cardiovascular risk in offspring in adulthood. STUDY DESIGN: To test our hypothesis, a 'n7AAc' (24 µg/d) or vehicle (saline) was given on gestation day 14 via miniosmotic pumps to sham-operated (sham) and Sprague-Dawley rat dams with reduced uterine perfusion pressure. Dams were allowed to deliver naturally, and pup weights were recorded within 12 hours after birth. Pups were aged to 16 weeks, at which time mean arterial pressure was measured and whole blood was collected to measure immune cells by flow cytometry, cytokines by enzyme-linked immunosorbent assay, and angiotensin II type 1 receptor autoantibodies by bioassay. A 2-way analysis of variance with the Bonferroni multiple comparison posthoc test was used for statistical analysis. RESULTS: There was no significant change in offspring birthweight of 'n7AAc'-treated male (5.63±0.09 g) or female (5.66±0.14 g) offspring from reduced uterine perfusion pressure dams compared with vehicle male (5.51±0.17 g) or female (5.74±0.13 g) offspring from reduced uterine perfusion pressure dams. In addition, 'n7AAc' treatment did not affect the birthweight of sham male (5.83±0.11 g) or female (5.64±0.12) offspring compared with vehicle sham male (5.811±0.15 g) or female (5.40±0.24 g) offspring. At adulthood, mean arterial pressure was unchanged in 'n7AAc' treated-male (133±2 mm Hg) and female (127±3 mm Hg) offspring from reduced uterine perfusion pressure dams compared with vehicle male (142±3 mm Hg) and female (133±5 mm Hg) offspring from reduced uterine perfusion pressure dams, the 'n7AAc'-treated sham male (133±3 mm Hg) and female (135±3 mm Hg) offspring, and vehicle sham male (138±4 mm Hg) and female (130±5 mm Hg) offspring. The circulating angiotensin II type 1 receptor autoantibodies were increased in vehicle male (10±2 ΔBPM) and female (14±2 ΔBPM) offspring from reduced uterine perfusion pressure dams and 'n7AAc'-treated male (11±2 ΔBPM) and female (11±2 ΔBPM) offspring from reduced uterine perfusion pressure dams compared with vehicle sham male (1±1 ΔBPM) and female (-1±1 ΔBPM) offspring and 'n7AAc'-treated sham male (-2±2 ΔBPM) and female (-2±2 ΔBPM) offspring. CONCLUSION: Our findings indicated that perinatal 7-amino acid sequence peptide treatment does not negatively impact offspring survival or weight at birth. Perinatal 'n7AAc' treatment did not prevent increased cardiovascular risk in offspring, but it also did not cause an increased cardiovascular risk in offspring with reduced uterine perfusion pressure compared with controls. Furthermore, perinatal 'n7AAc' treatment did not affect endogenous immunologic programming as observed by no change in circulating angiotensin II type 1 receptor autoantibodies in either sex of adult offspring from reduced uterine perfusion pressure dams.
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