AT1-AA Induced Placental Ischemia Contributes to Hypertension in Female Offspring

Abstract

Objective: Preeclampsia (PE), new-onset hypertension during the third trimester of pregnancy alongside other organ dysfunction, is associated with chronic inflammation and fetal growth restriction. Agonistic autoantibodies against the angiotensin II type 1 receptor (AT1-AA) are produced in PE women and induce a PE-like phenotype when infused into pregnant rats. AT1-AA is still present in maternal circulation up to eight years postpartum. We have shown that AT1-AA exposure during pregnancy contributes to impairment of cerebral blood flow in the postpartum period. Moreover, PE offspring are at higher risk for cardiovascular disease and hypertension but AT1-AA’s role in this elevated risk is unknown. The objective of this study was to determine if AT1-AA contributes to the risk for hypertension in PE offspring. Therefore, we hypothesized that AT1-AA infusion during pregnancy would cause offspring to have low birth weight and hypertension in adulthood. Methods: We infused AT1-AA (1:40) starting on gestational day (GD) 14 and allowed the dams to give birth on GD21. Birth weight was measured within 12 hours. Offspring were aged to 4 months. At that time, one male and female per litter were randomly selected to undergo carotid catheterization. The following day mean arterial pressure (MAP) was measured and blood and tissues were collected. Immune cells were measured by flow cytometry. Sex hormones were measured by mass spectroscopy. AT1-AA was measured by cardiomyocyte bioassay. Renal endothelin was measured by ELISA and RT-PCR. A two-way ANOVA was used for statistical analysis. Results: AT1-AA male and female offspring (6.1±0.1g, n=19, p<0.05; 5.8±0.1g, n=19, p<0.05) were larger at birth than NP male and female offspring (5.8±0.1g, n=11; 5.5±0.1g, n=11). Female AT1-AA offspring had elevated MAP (124±2 mmHg, n=14, p<0.05) compared to NP female offspring (110±5 mmHg, n=8) while male AT1-AA offspring had similar MAP to male NP offspring. Circulating cytolytic NK cells trended higher in female AT1-AA offspring (2.73±0.37 % gated, n=9, p=0.0949) compared to female NP offspring (1.66±0.31 % gated, n=6). Female AT1-AA offspring also had elevated progesterone (41.3±6.0 pg/μL, n=8, p=0.0556) compared to female NP offspring (26.9±4.9 pg/μL, n=7). Renal PPET expression was increased in female AT1-AA offspring (2.6±0.69 fold increase, n=4, p<0.05) compared to female NP offspring. Renal endothelin-1 was increased in female AT1-AA offspring (1.02±0.23 pg/mg, n=7, p=0.062) compared to female NP offspring (0.59±0.06 pg/mg, n=6). Male and female AT1-AA offspring had increased circulating AT1-AA (9.5±2.2 ΔBPM, n=6, p<0.0001; 7.9±0.9 ΔBPM, n=8, p<0.001) compared to male and female NP offspring (-0.4±.4 ΔBPM, n=7; -0.8±0.4 ΔBPM, n=4). Conclusion: These data demonstrate that AT1-AA infusion during pregnancy can predispose female offspring to have elevated blood pressure in adulthood. This study was supported by NIH grants RO1HD067541 (BL), F31HD110230 (NC), P20GM121334 (BL, LMA), HL151407 (DCC) and American heart association (AHA) early career award 19CDA34670055 (LMA). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.