Prion protein expression and functional importance in developmental angiogenesis: role in oxidative stress and copper homeostasis.

Abstract

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 (PrP(C)), a glycosyl phosphatidyl inositol-anchored glycoprotein, which we reported to be highly expressed in human placenta. Herein, we investigated the pathophysiological role of PrP(C) in Cu and oxidative stress homeostasis in vitro using human placenta and trophoblast cells, and in vivo using three strains of mice (C57Bl6, PrP(C) knockout mice [PrP(-/-)], and PrP(C) overexpressing mice [Tga20]).

RESULTS:

At the cellular level, PrP(C) 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 PrP(C) 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:

PrP(C) could serve as a marker for the idiopathic IUGR disease.

CONCLUSION:

These findings demonstrate the stress-protective role of PrP(C) during development, and propose PrP(C) dysregulation as a novel causative element of IUGR.

• Authors: Nadia Alfaidy, Sylvain Chauvet, Sandrine Donadio-Andrei, Aude Salomon, Yasmina Saoudi, Pierre Richaud, Catherine Aude-Garcia, Pascale Hoffmann, Annie Andrieux, Jean-Marc Moulis, Jean-Jacques Feige, Mohamed Benharouga
• Journal: Antioxidants & redox signaling (Antioxid Redox Signal) Vol. 18 Issue 4 Pg. 400-11 (Feb 01 2013) ISSN: 1557-7716 [Electronic] United States
• PMID: 22861352 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Hif1a protein, mouse
• Hypoxia-Inducible Factor 1, alpha Subunit
• PrPC Proteins
• Pregnancy Proteins
• Reactive Oxygen Species
• Copper

Topics

• Animals
• Cell Death
• Cell Hypoxia
• Cell Line
• Cell Movement
• Cell Proliferation
• Copper (blood)
• Cricetinae
• Female
• Fetal Growth Retardation (metabolism)
• Homeostasis
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Neovascularization, Physiologic
• Oxidative Stress
• Placenta (cytology, metabolism)
• PrPC Proteins (genetics, metabolism)
• Pregnancy
• Pregnancy Proteins (metabolism)
• Reactive Oxygen Species
• Transcriptome
• Trophoblasts (metabolism)
• Up-Regulation