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Background: Preeclampsia (PE), a life-threatening hypertensive pregnancy disorder, has long been speculated to be associated with placental hypoxia. Adenosine (Ado) is a signaling molecule well known to be induced by hypoxia. Ado levels are increased in the fetomaternal circulation of PE patients and correlated to its severity. However, the causative factors for its induction and pathophysiologic role of elevated Ado in PE are undetermined.Methods & Results: Using RT-PCR profiling of purinergic components in the human placentas, we found that CD73, a key enzyme producing extracellular Ado, was elevated most in the placentas of PE patients. To determine the exact role of elevated CD73 in Ado production, we took advantage of a well-established PE model: pregnant mice infused with angiotensin type 1 receptor agonistic antibody (AT1-AA), an emerging pathogenic factor known to contribute to PE. Similar to human studies, we found that both CD73 expression and Ado levels were significantly increased in the placentas of AT1-AA-injected pregnant mice compared to the controls. To determine whether elevated placental Ado is dependent on increased placental CD73 and contributes to pathophysiology of PE, we took both genetic and pharmacological approaches. We found that AT1-AA-mediated placental Ado production was reduced in CD73-deficient pregnant mice. As such, AT1-AA-induced features of PE including hypertension and proteinuria also significantly reduced (BP: 166 to 144 mmHg, proteinuria: 42 to 31 mg/g creatinine). Similarly, we found polyethylene glycol-linked adenosine deaminase (PEG-ADA), a drug that has successfully treated ADA-deficient patients by lowering Ado, ameliorated PE features significantly (BP: 170 to 141 mmHg, proteinuria: 39 to 28 mg/g creatinine). Mechanistically, we further revealed that HIF-1a is a key transcription factor underlying increased CD73 expression, Ado elevation, and subsequent sFlt-1 induction and disease development.Conclusions: Our studies revealed i) a pathologic nature of chronic elevated placental Ado in PE; ii) HIF-1a-dependent CD73 upregulation in placenta underlying Ado induction, sFlt-1 elevation and PE features; and iii) novel diagnostic markers and therapeutic possibilities for the disease.