Reciprocal upregulation of hypoxia-inducible factor-1α and persistently enhanced placental adenosine signaling contribute to the pathogenesis of preeclampsia

Recent evidence indicates that elevated placental adenosine signaling contributes to preeclampsia (PE). However, the molecular basis for the chronically enhanced placental adenosine signaling in PE remains unclear. Here, we report that hypoxia-inducible factor-1 alpha (HIF-1 alpha) is crucial for the enhancement of placental adenosine signaling. Utilizing a pharmacologic approach to reduce placental adenosine levels, we found that enhanced adenosine underlies increased placental HIF-1 alpha in an angiotensin receptor type 1 receptor agonistic autoantibody (AT(1)-AA)-induced mouse model of PE. Knockdown of placental HIF-1 alpha in vivo suppressed the accumulation of adenosine and increased ecto-5'-nucleotidase (CD73) and adenosine A(2B) receptor (ADORA2B) in the placentas of PE mouse models induced by AT(1)-AA or LIGHT, a TNF superfamily cytokine (TNFSF14). Human in vitro studies using placental villous explants demonstrated that increased HIF-1 alpha resulting from ADORA2B activation facilitates the induction of CD73, ADORA2B, and FLT-1 expression. Overall, we demonstrated that (a) elevated placental HIF-1 alpha by AT(1)-AA or LIGHT upregulates CD73 and ADORA2B expression and (b) enhanced adenosine signaling through upregulated ADORA2B induces placental HIF-1 alpha expression, which creates a positive feedback loop that promotes FLT-1 expression leading to disease development. Our results suggest that adenosine-based therapy targeting the malicious cycle of placental adenosine signaling may elicit therapeutic effects on PE.