Prion Protein Expression and Functional Importance in Developmental Angiogenesis: Role in Oxidative Stress and Copper Homeostasis

Aim: It has been convincingly shown that oxidative stress and toxicity by deregulated metals, such as copper (Cu), are tightly linked to the development of pre-eclampsia and intrauterine growth retardation (IUGR), the most threatening pathologies of human pregnancy. However, mechanisms implemented to control these effects are far from being understood. Among proteins that bind Cu and insure cellular protection against oxidative stress is the cellular prion protein (PrPC), a glycosyl phosphatidyl inositol-anchored glycoprotein, which we reported to be highly expressed in human placenta. Herein, we investigated the pathophysiological role of PrPC in Cu and oxidative stress homeostasis in vitro using human placenta and trophoblast cells, and in vivo using three strains of mice (C57Bl6, PrPC knockout mice [PrP-/-], and PrPC overexpressing mice [Tga20]). Results: At the cellular level, PrPC protection against oxidative stress was established in multiple angiogenic processes: proliferation, migration, and tube-like organization. For the animal models, lack (PrP-/-) or overexpression (Tga20) of PrPC in gravid mice caused severe IUGR that was correlated with a decrease in litter size, changes in Cu homeostasis, increase in oxidative stress response, development of hypoxic environment, failure in placental function, and maintenance of growth defects of the offspring even 7.5 months after delivery. Innovation: PrPC could serve as a marker for the idiopathic IUGR disease. Conclusion: These findings demonstrate the stress-protective role of PrPC during development, and propose PrPC dysregulation as a novel causative element of IUGR. Antioxid. Redox Signal. 18, 400-411.