Elevated placental adenosine signaling contributes to the pathogenesis of preeclampsia

Takayuki Iriyama, Kaiqi Sun, Nicholas F. Parchim, Jessica Li, Cheng Zhao, Anren Song, Laura A. Hart, Sean C. Blackwell, Baha M. Sibai, Lee Nien L. Chan, Teh Sheng Chan, M. John Hicks, Michael R. Blackburn, Rodney E. Kellems, Yang Xia

Research output: Contribution to journalArticlepeer-review

64 Scopus citations


Background: Preeclampsia is a prevalent hypertensive disorder of pregnancy and a leading cause of maternal and neonatal morbidity and mortality worldwide. This pathogenic condition is speculated to be caused by placental abnormalities that contribute to the maternal syndrome. However, the specific factors and signaling pathways that lead to impaired placentas and maternal disease development remain elusive. Methods and Results: Using 2 independent animal models of preeclampsia (genetically engineered pregnant mice with elevated adenosine exclusively in placentas and a pathogenic autoantibody-induced preeclampsia mouse model), we demonstrated that chronically elevated placental adenosine was sufficient to induce hallmark features of preeclampsia, including hypertension, proteinuria, small fetuses, and impaired placental vasculature. Genetic and pharmacological approaches revealed that elevated placental adenosine coupled with excessive A2B adenosine receptor (ADORA2B) signaling contributed to the development of these features of preeclampsia. Mechanistically, we provided both human and mouse evidence that elevated placental CD73 is a key enzyme causing increased placental adenosine, thereby contributing to preeclampsia. Conclusions: We determined that elevated placental adenosine signaling is a previously unrecognized pathogenic factor for preeclampsia. Moreover, our findings revealed the molecular basis underlying the elevation of placental adenosine and the detrimental role of excess placental adenosine in the pathophysiology of preeclampsia, and thereby, we highlight novel therapeutic targets.

Original languageEnglish (US)
Pages (from-to)730-741
Number of pages12
Issue number8
StatePublished - 2015


  • Adenosine
  • Animal
  • Hypertension
  • Models
  • Preeclampsia
  • Pregnancy

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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