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

• DOI: 10.1096/fj.201902583r
• Publication Date: 2020-01-13T05:31:10Z
• Authors: Takayuki Iriyama; Wei Wang; Nicholas F. Parchim; Seisuke Sayama; Keiichi Kumasawa; Takeshi Nagamatsu; Anren Song; Yang Xia; Rodney E. Kellems
• Keywords: Adenosine A3 receptor; Adenosine A2B receptor; Adenosine kinase; Purinergic Signalling; Adenosine A2A receptor

Recent evidence indicates that elevated placental adenosine signaling contributes to preeclampsia (PE). However, the molecular basis for chronically enhanced in PE remains unclear. Here, we report hypoxia-inducible factor-1α (HIF-1α) is crucial enhancement of signaling. Utilizing a pharmacologic approach reduce levels, found underlies increased HIF-1α an angiotensin receptor type 1 agonistic autoantibody (AT1 -AA)-induced mouse model PE. Knockdown vivo suppressed accumulation and ecto-5'-nucleotidase (CD73) A2B (ADORA2B) placentas models induced by AT1 -AA or LIGHT, TNF superfamily cytokine (TNFSF14). Human vitro studies using villous explants demonstrated resulting from ADORA2B activation facilitates induction CD73, ADORA2B, FLT-1 expression. Overall, (a) LIGHT upregulates CD73 expression (b) through upregulated induces expression, which creates positive feedback loop promotes leading disease development. Our results suggest adenosine-based therapy targeting malicious cycle may elicit therapeutic effects on