Low‐dose aspirin reduces hypoxia‐induced sFlt1 release via the JNK/AP‐1 pathway in human trophoblast and endothelial cells

Abstract

Pre‐eclampsia (PE) is a serious hypertensive disorder of pregnancy that remains a leading cause of perinatal and maternal morbidity and mortality worldwide. Placental ischemia/hypoxia and the secretion of soluble fms‐like tyrosine kinase 1 (sFlt1) into maternal circulation are involved in the pathogenesis of PE. Although low‐dose aspirin (LDA) has beneficial effects on the prevention of PE, the exact mechanisms of action of LDA, particularly on placental dysfunction, and sFlt1 release, have not been well investigated. This study aimed to determine whether LDA exists the protective effects on placental trophoblast and endothelial functions and prevents PE‐associated sFlt1 release. First, we observed that LDA mitigated hypoxia‐induced trophoblast apoptosis, showed positive effects on trophoblast cells migration and invasion activity, and increased the tube‐forming activity of human umbilical vein endothelial cells (HUVECs). In addition, LDA decreased hypoxia‐induced sFlt1 production, and the c‐Jun NH2‐terminal kinase/activator protein‐1 (JNK/AP‐1) pathway was shown to mediate the induction of sFlt1. Moreover, the transcription factor AP‐1 was confirmed to regulate the Flt1 gene expression by directly binding to the Flt1 promoter in luciferase assays. The result of chromatin immunoprecipitation assays further demonstrated that LDA could directly decrease the expression of the transcription factor AP‐1, and thus decrease sFlt1 production. Finally, the effects of LDA on sFlt1 production were proved in human placental explants. Taken together, our data show the protective effects of LDA against trophoblast and endothelial cell dysfunction and reveal that the LDA‐mediated inhibition of sFlt1 via the JNK/AP‐1 pathway may be a potential cellular/molecular mechanism for the prevention of PE.

Pathogenesis of Preeclampsia and Therapeutic Approaches Targeting the Placenta

“…The transcription factor AP-1 regulates sFlt-1 production by binding to the Flt-1 promoter. LDA mitigates the hypoxia-induced apoptosis of trophoblasts, and thus trophoblast migration and invasion capabilities are restored [ 138 ].…”

AJOG opens editorial office in China: Professor Huixia Yang appointed Editor

“…preeclampsia through its actions in inhibiting nuclear-factor kappa B (NFkB) and the release of soluble Flt-1. 2,3 Her main focus has been on the diagnosis, management, and prevention of metabolic syndrome in the context of gestational diabetes mellitus 4 . The Yang lab is the Beijing Key Laboratory of Maternal Fetal Medicine of Gestational Diabetes Mellitus, and she has had cooperation with some labs in the Chinese Academy of Science for many years.…”

Long Non-Coding RNA Nuclear-Enriched Abundant Transcript 1 (NEAT1) Represses Proliferation of Trophoblast Cells in Rats with Preeclampsia via the MicroRNA-373/FLT1 Axis

“…More recently, miR-145-5p was found to enhance trophoblast cell proliferation and invasion by reducing FLT1 expression [ 27 ]. Inhibition of FLT1 by low-dose aspirin may be a promising cellular and molecular mechanism for the prevention of PE [ 28 ]. In addition to its effects on trophoblast cells, FLT1 was also shown to be involved in fetoplacental endothelial cell migration and angiogenesis [ 29 ], suggesting its tight correlation with pregnancy.…”