Protein Phosphatase 2A Activation Via ApoER2 in Trophoblasts Drives Preeclampsia in a Mouse Model of the Antiphospholipid Syndrome

• Published in: Circulation research Vol. 129; no. 7; pp. 735 - 750
• Main Authors: Chu, Haiyan, Sacharidou, Anastasia, Nguyen, An, Li, Chun, Chambliss, Ken L., Salmon, Jane E., Shen, Yu-Min, Lo, Julie, Leone, Gustavo W., Herz, Joachim, Hui, David Y., Marciano, Denise K., Abrahams, Vikki M., Natale, Bryony V., Montalbano, Alina P., Xiao, Xue, Xu, Lin, Natale, David R., Shaul, Philip W., Mineo, Chieko
• Format: Journal Article
• Language: English
• Published: United States Lippincott Williams & Wilkins 17.09.2021
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Animals; Antibodies, Antiphospholipid - blood; Antiphospholipid Syndrome - complications; Antiphospholipid Syndrome - metabolism; Apoptosis Regulatory Proteins - metabolism; Cell Line; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; LDL-Receptor Related Proteins - metabolism; Mice; Mice, Inbred C57BL; Pre-Eclampsia - etiology; Pre-Eclampsia - metabolism; Pregnancy; Protein Phosphatase 2 - metabolism; Trophoblasts - metabolism; antiphospholipid syndrome; placenta; endoglin; preeclampsia; proteinuria; trophoblasts
• ISSN: 0009-7330; 1524-4571; 1524-4571
• DOI: 10.1161/CIRCRESAHA.120.318941

Preeclampsia (PE) is a leading cause of morbidity and mortality during pregnancy. The initiating processes in PE are poorly understood, and the only effective intervention is premature delivery, which threatens the well-being of the child. The Antiphospholipid Syndrome (APS), which is characterized by circulating antiphospholipid antibodies (aPL), is a common risk factor for PE, and also for fetal demise, premature birth and intrauterine growth restriction. This work presents an animal model of APS-related PE, revealing that aPL administration to pregnant mice induces PE and fetal compromise via ApoER2 in trophoblasts. Mechanistically, via ApoER2, aPL activate PP2A, which upregulates MMP14 and HIF1α, the latter via dephosphorylation of PHD2, leading to increased production of soluble endoglin, which is a known driver of PE. A role for PP2A in PE pathogenesis is revealed, and linkage of PP2A to PHD2 and HIF1α is demonstrated in placentas from both APS patients and women with PE from causes other than APS. As importantly, pharmacologic inhibition of PP2A affords full protection from both aPL-induced PE and the fetal complications. Future research should interrogate how PP2A is activated in PE not associated with APS, and how PP2A can be targeted to combat PE.