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

Journal of Biomedical Science

Guanlin Li¹  Guangming Cao²  Yangyu Zhao³  Yongqing Wang³  Yu-Xia Li⁴  Yeling Ma⁴  Xuan Shao⁵  Yan-Ling Wang⁵ 

[1] Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing, China;Department of Obstetrics and Gynecology, Beijing Chao-Yang Hospital, Beijing, China;Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China;State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China;State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China;Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China;University of the Chinese Academy of Sciences, Beijing, China;

关键词: Preeclampsia;    Met;    Hypoxia;    Endocytosis;    Ubiquitin degradation;    CAV-1;    Cbl;   

DOI  :  10.1186/s12929-022-00791-5

来源: Springer

【 摘 要 】

BackgroundPreeclampsia (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.ResultsWe 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.ConclusionsThese 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.

【 授权许可】

CC BY