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- W4319298322 abstract "Conjugated bile acids (BA) are significantly elevated in several liver pathologies and in the metastatic lymph node (LN). However, the effects of BAs on pathological lymphangiogenesis remains unknown. The current study explores the effects of BAs on lymphangiogenesis. BA levels were elevated in the LN and serum of Mdr2−/− mice (model of sclerosing cholangitis) compared to control mice. Liver and LN tissue sections showed a clear expansion of the lymphatic network in Mdr2−/− mice, indicating activated lymphangiogenic pathways. Human lymphatic endothelial cells (LECs) expressed BA receptors and a direct treatment with conjugated BAs enhanced invasion, migration, and tube formation. BAs also altered the LEC metabolism and upregulated key metabolic genes. Further, BAs induced the production of reactive oxygen species (ROS), that in turn phosphorylated the redox-sensitive kinase p90RSK, an essential regulator of endothelial cell dysfunction and oxidative stress. Activated p90RSK increased the SUMOylation of the Prox1 transcription factor and enhanced VEGFR3 expression and 3-D LEC invasion. BA-induced ROS in the LECs, which led to increased levels of Yes-associated protein (YAP), a lymphangiogenesis regulator. The suppression of cellular YAP inhibited BA-induced VEGFR3 upregulation and lymphangiogenic mechanism. Overall, our data shows the expansion of the lymphatic network in presclerotic liver disease and establishes a novel mechanism whereby BAs promote lymphangiogenesis." @default.
- W4319298322 created "2023-02-07" @default.
- W4319298322 creator A5002587926 @default.
- W4319298322 creator A5007747575 @default.
- W4319298322 creator A5008186445 @default.
- W4319298322 creator A5032076733 @default.
- W4319298322 creator A5045220703 @default.
- W4319298322 creator A5064167770 @default.
- W4319298322 creator A5064427433 @default.
- W4319298322 creator A5078210704 @default.
- W4319298322 date "2023-02-06" @default.
- W4319298322 modified "2023-09-30" @default.
- W4319298322 title "Conjugated Bile Acids Promote Lymphangiogenesis by Modulation of the Reactive Oxygen Species–p90RSK–Vascular Endothelial Growth Factor Receptor 3 Pathway" @default.
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