Hypoxic stress disrupts HGF/Met signaling in human trophoblasts: implications for the pathogenesis of preeclampsia

Abstract

Background Preeclampsia (PE), a placenta-associated pregnancy complication, is the leading cause of maternal and perinatal morbidity and mortality. Met/Erk signaling is inhibited in the placentas of patients with early-onset preeclampsia (E-PE), but the underlying mechanisms remain elusive. In this study, the expression modes of Met and endocytic vesicles in normal and preeclamptic placentas were compared. Biotinylation internalization/recycling assays were used to measure the endocytosis of Met under hypoxia and normoxia in HTR8/SVneo cells. In addition, the expression level of Cbl, a specific E3 ligase of Met, was measured under hypoxia and normoxia, and the endocytosis of Met was studied by using confocal microscopy. Results We found considerable intracellular accumulation of Met, which was colocalized with caveolin-1 (CAV-1), in trophoblasts from E-PE placentas. Prolonged hypoxic stimulation led to the remarkable augmentation of CAV-1-mediated Met endocytosis in HTR8/SVneo cells. In addition, the expression of Cbl was substantially repressed by sustained hypoxia, disrupting ubiquitin degradation and the subsequent intracellular accumulation of Met in HTR8/SVneo cells. The abnormal degradation of Met hampered the ability of hepatocyte growth factor (HGF) to promote trophoblast cell invasion. In E-PE placentas, aberrant upregulation of CAV-1 and downregulation of Cbl were observed in parallel to the intracellular accumulation of Met. Conclusions These findings reveal that prolonged hypoxic stress induces the augmentation of endocytosis and repression of ubiquitin-mediated Met degradation, which leads to the impaired regulation of trophoblast invasion by HGF/Met signaling. These data provide novel evidence for elucidating the pathogenesis of preeclampsia, especially of the early-onset subtype.

Differential Expression of NME4 in Trophoblast Stem-Like Cells and Peripheral Blood Mononuclear Cells of Normal Pregnancy and Preeclampsia

“…Many studies mentioned that dysfunction of the placenta in PE induced prolonged hypoxic stress. 60 61 Our results showed that oxidation-reduction process related protein TRX tend to up-regulated in model of early pregnancy of PE. Previous studies have reported that TRX is rich in the human placenta, suggesting its protective role in trophoblasts.…”

Investigating the molecular mechanism of traditional Chinese medicine for the treatment of placental syndromes by influencing inflammatory cytokines using the Mendelian randomization and molecular docking technology

“…observed that upon binding to its receptor Met, HGF can activate the downstream Erk pathway, facilitating trophoblast invasion and maintaining a healthy pregnancy. While hypoxia can disrupt the regulation of the HGF/Met signaling pathway, and promoting the occurrence of PE ( 30 ). Chaudhary et al.…”

Microscopic polyangiitis plasma-derived exosomal miR-1287-5p induces endothelial inflammatory injury and neutrophil adhesion by targeting CBL

“…Hypoxia is a typical microenvironmental feature of most autoimmune diseases, affecting a variety of physiological processes ( Deng et al, 2022 ; Li et al, 2022b ; Lohrasbi et al, 2022 ). One study has shown that sustained hypoxia stress can repress the CBL expression and disrupt ubiquitin degradation, leading to impaired regulation of human trophoblasts, which is the main mechanism of preeclampsia ( Li et al, 2022a ). However, it has also been shown that hypoxia induces an increase in CBL expression in H9c2 cells.…”