Beta-Arrestin1 Prevents Preeclampsia by Downregulation of Mechanosensitive AT1-B2 Receptor Heteromers

• Published in: Cell Vol. 176; no. 1-2; pp. 318 - 333.e19
• Main Authors: Quitterer, Ursula, Fu, Xuebin, Pohl, Armin, Bayoumy, Karam M., Langer, Andreas, AbdAlla, Said
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10-01-2019
• Subjects: AGTR1; amlodipine; angiotensin II; ARRB1; BDKRB2; biased agonist; bradykinin; heterodimer; mechanosensitivity; preeclampsia; heterodimer; mechanosensitivity; angiotensin II; biased agonist; AGTR1; BDKRB2; bradykinin; ARRB1; preeclampsia; amlodipine
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2018.10.050

Preeclampsia is the most frequent pregnancy-related complication worldwide with no cure. While a number of molecular features have emerged, the underlying causal mechanisms behind the disorder remain obscure. Here, we find that increased complex formation between angiotensin II AT1 and bradykinin B2, two G protein-coupled receptors with opposing effects on blood vessel constriction, triggers symptoms of preeclampsia in pregnant mice. Aberrant heteromerization of AT1-B2 led to exaggerated calcium signaling and high vascular smooth muscle mechanosensitivity, which could explain the onset of preeclampsia symptoms at late-stage pregnancy as mechanical forces increase with fetal mass. AT1-B2 receptor aggregation was inhibited by beta-arrestin-mediated downregulation. Importantly, symptoms of preeclampsia were prevented by transgenic ARRB1 expression or a small-molecule drug. Because AT1-B2 heteromerization was found to occur in human placental biopsies from pregnancies complicated by preeclampsia, specifically targeting AT1-B2 heteromerization and its downstream consequences represents a promising therapeutic approach.
[Display omitted]
•The beta-arrestin-biased agonist, TRV027, targets AT1-B2 and prevents preeclampsia•AT1-B2 enhances the vascular sensitivity to angiotensin II and mechanical stimulation•Increased vascular AT1-B2 in pregnant mice is a sufficient cause for preeclampsia•Transgenic ARRB1 counteracts preeclampsia symptoms by downregulation of AT1-B2
This paper provides a mechanistic understanding of the causes of preeclampsia and uses the newly gained insights to explore treatment for the condition.