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

49 Pages Posted: 7 Jan 2019 Sneak Peek Status: Published

See all articles by Ursula Quitterer

Ursula Quitterer

ETH Zurich - Molecular Pharmacology; University of Zurich - Institute of Pharmacology and Toxicology

Xuebin Fu

Stanford University - Department of Microbiology and Immunology

Armin Pohl

Roche Diagnostics International AG

Karam M. Bayoumy

Ain Shams University - Clinic of Obstetrics and Gynecology

Andreas Langer

ETH Zurich - Molecular Pharmacology

Said AbdAlla

ETH Zurich - Molecular Pharmacology

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Abstract

Preeclampsia is the most frequent pregnancy-related complication worldwide with no cure. In search for underlying pathomechanisms, we found that transgenic AT1-B2 receptor expression under control of the smooth muscle-specific SM22alpha promoter was sufficient to trigger symptoms of preeclampsia in pregnant mice. Vascular smooth muscle cells from AT1-B2-transgenic mice showed hypersensitive calcium signaling and increased mechanosensitivity. This phenotype was attributed to AT1-B2 heteromerization because down-regulation of AT1- B2 by the beta-arrestin-biased AT1 antagonist, SII, reversed AT1-B2mediated effects in vascular smooth muscle cells whereas the unbiased AT1 antagonist losartan was ineffective. In vivo, down-regulation of AT1B2 by lentiviral transduction of ARRB1-S412A inhibited preeclampsia. Likewise, induction of Arrb1 by the small-molecule drug amlodipine, promoted AT1-B2 down-regulation, and prevented AT1-B2-induced mechanosensitivity and symptoms of preeclampsia. The deduced treatment strategy could improve the therapy of human preeclampsia because vascular AT1-B2 heteromerization was also identified as a characteristic feature of placental biopsies from pregnancies complicated by preeclampsia.

Suggested Citation

Quitterer, Ursula and Fu, Xuebin and Pohl, Armin and Bayoumy, Karam M. and Langer, Andreas and AbdAlla, Said, Beta-Arrestin1 Prevents Preeclampsia by Down-Regulation of Mechanosensitive AT1-B2 Receptor Heteromers (2018). Available at SSRN: https://ssrn.com/abstract=3188449 or http://dx.doi.org/10.2139/ssrn.3188449
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Ursula Quitterer (Contact Author)

ETH Zurich - Molecular Pharmacology ( email )

Winterthurerstrasse 190
Zürich, 8057
Switzerland

University of Zurich - Institute of Pharmacology and Toxicology

Winterthurerstrasse 190
Zürich, CH-8057
Switzerland

Xuebin Fu

Stanford University - Department of Microbiology and Immunology

Stanford, CA 94305
United States

Armin Pohl

Roche Diagnostics International AG

Forrenstrasse 2
Rotkreuz, CH-6343
Switzerland

Karam M. Bayoumy

Ain Shams University - Clinic of Obstetrics and Gynecology

Cairo
Egypt

Andreas Langer

ETH Zurich - Molecular Pharmacology

Winterthurerstrasse 190
Zürich, 8057
Switzerland

Said AbdAlla

ETH Zurich - Molecular Pharmacology

Winterthurerstrasse 190
Zürich, 8057
Switzerland

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