Beta-Arrestin1 Prevents Preeclampsia by Down-Regulation of Mechanosensitive AT1-B2 Receptor Heteromers
49 Pages Posted: 7 Jan 2019 Publication Status: PublishedMore...
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.
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