Chantal Kinsey

Introduction. Preeclampsia is the leading cause of death of pregnant women and the most common pregnancy complication with gestational hypertension leading to end-organ dysfunction.^1,2 The mechanism by which preeclampsia induces organ damage is similar to other hypertensive conditions mediated by the upregulation of renin-angiotensin system (RAS) and downregulation of kallikrein-kinin system (KKS).^1,2 However, their interaction for developing preeclampsia remains incompletely understood. The angiotensin II (AngII) type 1 receptor (AT1R) and bradykinin B2 receptor (B2R) heterodimer (AT1-B2R) induced from damaged endothelium and inflammation has been shown to cause aberrant G-protein signaling, increase smooth muscle contraction and AngII hypersensitivity, develop AT1R autoantibodies, and increase mechanoreceptor sensitivity in later stages of pregnancy.^1–5 The formation of AT1-B2R might contribute to preeclampsia.⁶ The purpose of this paper is to identify the contribution of AT1-B2R heterodimer to preeclampsia and the strategy for this disease treatment. Methods. The preeclampsia pathology development was tested in guinea pigs by administering subcutaneous infusions of AngII, bradykinin B2 receptor antagonist, or both alongside a control group during the period of maximal trophoblast invasion and placental development. 26 days after infusions, organs were measured, and trophoblast invasion of spiral arteries was defined in the uteroplacental units by immunocytochemistry.³ In another study, transgenic mice were generated with smooth muscle expression of AT1 and B2 receptors under the control of the SM22-alpha promoter. The vascular smooth muscle mechanics and biochemistry were assessed  with the development of preeclampsia.¹ The allosteric ligands of the AT1R as autoantibody blockers were developed based on high-resolution structural knowledge and molecular dynamics simulation.² Results. In the guinea pig study, upregulation of RAS and downregulation of  KKS displayed decreased intraluminal replacement of endothelium by extravillous trophoblasts (EVT), decreased EVT invasion of myometrial spiral arteries, increased fetal loss with hypertension, and developed preeclampsia-like symptoms.³ AT1-B2R transgenic mice showed enhanced vascular contraction/sensitivity to AngII and mechanical stimulation. Downregulation of AT1-B2R counteracted symptoms of preeclampsia.¹ The autoantibody IgG potentiated calcium response and modulated the actions induced by AT1R agonists.²  The compounds that exerted negative allosteric modulator effects on AngII were also identified and the allosteric ligands were shown to block autoimmune antibodies. Conclusion. The unbalanced RAS and KKS with the formation of AT1-B2R heterodimer play a crucial role in the development of preeclampsia. The approaches of downregulating AT1-B2R and developing allosteric ligands for modulation of the AT1 receptor with preventing autoantibody binding are potential strategies for treating preeclampsia.

1.  Quitterer U, Fu X, Pohl A, Bayoumy KM, Langer A, AbdAlla S. Beta-Arrestin1 prevents preeclampsia by downregulation of mechanosensitive AT1-B2 receptor heteromers. Cell. 2019;176(1-2):318-333.e19. doi:10.1016/J.CELL.2018.10.050/ATTACHMENT/6661ED04-D198-4713-8FA6-A66634C926A9/MMC1.PDF
2. Singh KD, Jara ZP, Harford T, et al. Novel allosteric ligands of the angiotensin receptor AT1R as autoantibody blockers. Proc Natl Acad Sci U S A. 2021;118(33). doi:10.1073/PNAS.2019126118/-/DCSUPPLEMENTAL
3. Valdés G, Schneider D, Corthorn J, Ortíz R, Acuña S, Padilla O. Administration of angiotensin II and a bradykinin B2 receptor blocker in midpregnancy impairs gestational outcome in guinea pigs. Reprod Biol Endocrinol. 2014;12(1):1-8. doi:10.1186/1477-7827-12-49/FIGURES/4
4. Anton EL, Fernandes D, Assreuy J, da Silva-Santos JE. Bradykinin increases BP in endotoxemic rat: functional and biochemical evidence of angiotensin II AT1/bradykinin B2 receptor heterodimerization. Br J Pharmacol. 2019;176(14):2608. doi:10.1111/BPH.14685
5. Wu H, Wang Y, Wang G, et al. A bivalent antihypertensive vaccine targeting L-type calcium channels and angiotensin AT1 receptors. Br J Pharmacol. 2020;177(2):402-419. doi:10.1111/bph.14875
6. Quitterer U, Abdalla S. Pathological AT1R-B2R protein aggregation and preeclampsia. Cells. 2021;10(10). doi:10.3390/CELLS10102609