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

Author:
Quitterer, Ursula, Fu, Xuebin, Pohl, Armin, Bayoumy, Karam M., Langer, Andreas, AbdAlla, Said
Source:
Cell 2019 v.176 no.1-2 pp. 318-333.e19
ISSN:
0092-8674
Subject:
G-protein coupled receptors, angiotensin II, biopsy, blood vessels, bradykinin, calcium signaling, drugs, forces, genetically modified organisms, humans, mice, pre-eclampsia, pregnancy, smooth muscle
Abstract:
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.
Agid:
6282776