1. Beta-Arrestin1 Prevents Preeclampsia by Downregulation of Mechanosensitive AT1-B2 Receptor Heteromers.
- Author
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Quitterer, Ursula, Fu, Xuebin, Pohl, Armin, Bayoumy, Karam M., Langer, Andreas, and AbdAlla, Said
- Subjects
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PREECLAMPSIA , *ARRESTINS , *DOWNREGULATION , *PREGNANCY complications , *SYMPTOMS , *MUSCLE physiology - Abstract
Summary 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. Graphical Abstract Highlights • 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. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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