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

• Published in: American journal of obstetrics & gynecology MFM 2023-06, Vol.5 (6), p.100945, Article 100945
• Main Authors: Solise, Dylan, Campbell, Nathan, Ashraf, Usman, Herrock, Owen, Crudup, Breland, Mallette, Jordan, Willis, Alex, Rawls, Adam Z., Turner, Ty, Cockrell, Kathy, Zheng, Baoying, Deer, Evangeline, Amaral, Lorena, Alexander, Barbara T., Lamarca, Babbette
• Format: Article
• Language: English
• Subjects: Animals; autoantibodies; Autoantibodies - pharmacology; Birth Weight; Blood Pressure; Female; Humans; Hypertension; immunology; Male; offspring; Perfusion; Pre-Eclampsia - prevention & control; preeclampsia; Pregnancy; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1 - metabolism
• ISSN: 2589-9333; 2589-9333
• DOI: 10.1016/j.ajogmf.2023.100945

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. 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. 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. 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 arteri