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CD73-mediated increased placental adenosine signaling via A2B adenosine receptor contributes to the pathogenesis of preeclampsia
2016 Volume 31 Pages 16-23
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2016 Volume 31 Pages 16-23
<Objectives>
Adenosine (Ado) is a signaling molecule known to be induced by hypoxia and to be involved in the pathophysiology of various disease. We recently reported that Ado levels and the enzymatic activity of CD73, an enzyme that converts AMP to Ado, are elevated in preeclampsia (PE) patient placentas. However, pathophysiological role of placental CD73 in PE remains unknown. Here, we assessed the function of CD73 and the significance of Ado signaling in vivo by using angiotensin II type 1 receptor agonistic autoantibody (AT1-AA)-induced PE mouse model.
<Methods>
PE mouse model induced by AT1-AA isolated from PE patient sera was conducted. AT1-AA-induced phenotypes of wild type (WT), CD73-deficient (Cd73-/-), and A2B Ado receptor (ADORA2B) -deficient (Adora2b-/-) dams were examined. The research protocol was approved by our institution and informed consent was obtained from all patients.
<Results>
Placental Ado levels and CD73 expression were significantly induced in AT1-AA-treated WT dams. We found that placental Ado levels were significantly reduced in AT1-AA-treated Cd73-/- dams compared with WT dams. Additionally, AT1-AA-induced PE features, hypertension and proteinuria, were attenuated in Cd73-/- dams compared with WT dams. Expression analysis of Ado receptors revealed that only ADORA2B expression was significantly elevated in the placenta of AT1-AA-treated WT dams. We discovered that PE features were significantly suppressed in AT1-AA-treated Adora2b-/- dams compared with WT dams.
<Conclusions>
Our results reveled that AT1-AA-induced placental CD73 promotes the production of Ado leading to the development of PE thorough the activation of ADORA2B.
