Morgan Sheppard

Background: Preeclampsia is a multisystemic condition which develops after 20 weeks of gestation.^1,2 It is identified as new onset hypertension and is frequently accompanies with systemic complications such as proteinuria, eclampsia, acute kidney injury, hepatic injury, and fetal growth restriction.^1,2 Preeclampsia is considered the most common cause of maternal and fetal morbidity and mortality during pregnancy, affecting 2-10% of all pregnancies in the United States.³ It has a much higher rate among African American women compared to other ethnicities.³ Risk factors include chronic hypertension, pregestational diabetes mellitus, obesity and prior preeclampsia.² Many patients with preeclampsia face lifelong repercussions such as neurological and cardiovascular risk.³ Preeclampsia first develops due to impairment of trophoblast invasion and inability of the spiral artery to remodel, resulting in decrease placental perfusion.¹ This placental stress causes release of inflammatory mediators initiating the systemic maternal injury.¹ One of these mediators is Angiotensin II type 1 receptor agonistic autoantibodies (AT1-AA), which activates AT1R.² Activation results in promotion of vasoconstriction, oxidative stress, and endothelial dysfunction.² Current treatment of preeclampsia is limited to delivery of the baby/placenta and symptoms management using antihypertensives and anticonvulsants.⁴ Aspirin can also be given as a preventative measure.⁴ Targeting and neutralizing AT1-AA may prove to be a promising new therapeutic strategy addressing the inflammatory mediators of preeclampsia.

Objective: This narrative review investigates if the neutralization of AT1-AA can interfere with the pathogenic process leading to the preeclampsia phenotype.

Search Methods: A literature search was conducted in the PubMed online database from 2017 to 2025 using the following keywords: “preeclampsia,” “AT1-AA,” and “angiotensin II type 1 receptor agonistic autoantibody.”

Results: AT1-AA has been proven to initiate many downstream signaling pathways such as MAPK/ERK and NF-kB, which allows it to contribute to endothelial dysfunction, production of inflammatory cytokines, and placental apoptosis.² Some preclinical studies using the reduced uterine prefusion pressure (RUPP) rat model demonstrated a consistent benefit of neutralizing AT1-AA and many associated outcomes.  RUPP primed B2 cells transferred hypertension and increased levels of AT1-AA to normal pregnant rats, while an AT1-AA blockade reduced the hypertension.⁵ AT1-AA neutralization also reduced the mitochondrial ROS and improved the mitochondrial respiration in both the placenta and renal tissues.⁶ Using preeclamptic postpartum serum injected into RUPP rates also induced the endothelial mitochondrial injury, which effects were then attenuated using the neutralizing peptide n7AAc.⁷ Research also supports that AT1-AA inhibition improves uterine artery blood flow, fetal weight, and placental microRNA expression.⁸ In postpartum RUPP rats, hypertension and cardiac mitochondrial dysfunction persisted but improved with the introduction of AT1 -AA inhibition.⁹

Conclusion: In multiple preclinical models, AT1-AA neutralization resulted in an improvement of maternal blood pressure, oxidative stress, endothelial function, fetal growth and long-term postpartum outcomes. This emphasizes the role of AT1-AA as an actionable therapeutic target and driver of preeclampsia. The evidence presented thus far supports the continued investigation of AT1-AA as a risk identifier in pregnant patients as well. Since current research is mainly preclinical, future research should involve human trials to establish clinical efficacy, safety, and optimal timing for affective interventions. Ultimately, deepening the understanding of this inflammatory pathway could result in a more targeted and individualized treatment plan that extends beyond delivery and symptom management.

Works Cited

1. Miller D, Motomura K, Galaz J, et al. Cellular immune responses in the pathophysiology of preeclampsia. J Leukoc Biol. 2022;111(1):237-260. doi:10.1002/JLB.5RU1120-787RR
2. Wang J, Shan L, Zhao Y, Cao H, Lan S, Yan Y. Role of agonistic autoantibodies to the angiotensin II type 1 receptor (AT1-AA) in pathogenesis of preeclampsia. Glob Med Genet. 2025;12(2):100041. doi:10.1016/j.gmg.2025.100041
3. Roberts JM. Preeclampsia epidemiology(ies) and pathophysiology(ies). Best Pract Res Clin Obstet Gynaecol. 2024;94:102480. doi:10.1016/j.bpobgyn.2024.102480
4. Ryan K, McGrath L, Brookfield K. Hypertension management in pregnancy. Annu Rev Med. 2025;76(1):315-326. doi:10.1146/annurev-med-050423-085626
5. Herrock OT, Deer E, Amaral LM, et al. B2 cells contribute to hypertension and natural killer cell activation possibly via AT1-AA in response to placental ischemia. Am J Physiol Renal Physiol. 2023;324(2):F179-F192. doi:10.1152/ajprenal.00190.2022
6. Vaka VR, Cunningham MW, Deer E, et al. Blockade of endogenous angiotensin II type I receptor agonistic autoantibody activity improves mitochondrial reactive oxygen species and hypertension in a rat model of preeclampsia. Am J Physiol Regul Integr Comp Physiol. 2020;318(2):R256-R262. doi:10.1152/ajpregu.00179.2019
7. Deer E, Vaka VR, McMaster KM, et al. Vascular endothelial mitochondrial oxidative stress in response to preeclampsia: a role for angiotensin II type 1 autoantibodies. Am J Obstet Gynecol MFM. 2021;3(1):100275. doi:10.1016/j.ajogmf.2020.100275
8. Ashraf UM, Hall DL, Campbell N, et al. Inhibition of the AT1R agonistic autoantibody in a rat model of preeclampsia improves fetal growth in late gestation. Am J Physiol Regul Integr Comp Physiol. 2022;323(5):R670-R681. doi:10.1152/ajpregu.00122.2022
9. Booz GW, Kennedy D, Bowling M, et al. Angiotensin II type 1 receptor agonistic autoantibody blockade improves postpartum hypertension and cardiac mitochondrial function in rat model of preeclampsia. Biol Sex Differ. 2021;12(1):58. doi:10.1186/s13293-021-00396-x