ACE2 and CD47 Interactions to Regulate Fetal Growth

Placental insufficiency is associated with abnormal maternal and fetal outcomes. We previously demonstrated that angiotensin converting enzyme 2 (ACE2) knockout (KO) mice develop placental hypoxia at day 14 of gestation (GD14) as measured by photoacoustic imaging and higher expression of hypoxia markers (PMID: 28842425). Cell surface glycoprotein CD47 is induced by hypoxia and can disrupt inflammatory and nitric oxide pathways. Our data demonstrate that placental hypoxia is associated with upregulation of CD47, increase in superoxide production, and dysregulation of nitric oxide and IL-6-associated pathways. Our data also show that p62 protein levels increase in total placental homogenates of ACE2 KO mice. Accumulation of p62 indicates the potential inhibition of autophagy. Since CD47 can inhibit autophagy in renal and cancer cells, it is possible that increased CD47 downregulates the initiation of autophagy in the placenta of FGR mice. These studies established a novel mechanism leading to the development of fetal growth restriction which is dependent on ACE2 and CD47/TSP-1 interactions in the placenta.