- 作者: Guanlin Li, Yongqing Wang, Guangming Cao, Yeling Ma, Yu-Xia Li, Yangyu Zhao, Xuan Shao & Yan-Ling Wang
- 作者服務機構: 1.Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China 2.Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing, China 3.Department of Obstetrics and Gynecology, Beijing Chao-Yang Hospital, Beijing, China 4.Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China 5.Guanlin Li Yongqing Wang and Guangming Cao contributed equally and should be regarded as joint first authors. 6.State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China 7.University of the Chinese Academy of Sciences, Beijing, China
- 中文摘要:
- 英文摘要:
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. - 中文關鍵字:
- 英文關鍵字: Preeclampsia, Met, Hypoxia, Endocytosis, Ubiquitin degradation, CAV-1, Cbl