Vascular endothelial growth factor stimulates rat cholangiocyte proliferation via an autocrine mechanism
| Autor: | Yoshiyuki Ueno, Ramona Reichenbach, Marco Marzioni, Domenico Alvaro, Julie Venter, Giammarco Fava, Paolo Onori, George Stoica, Shannon Glaser, Sharon De Morrow, Gianfranco Alpini, Silvia Taffetani, Cynthia J. Meininger, Heather Francis, Ryun Summers, Barbara Barbaro, Eugenio Gaudio, Antonio Franchitto |
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| Jazyk: | angličtina |
| Rok vydání: | 2006 |
| Předmět: |
Male
Vascular Endothelial Growth Factor A medicine.medical_specialty Protein Kinase C-alpha Vascular Endothelial Growth Factor C Cholangiocyte proliferation Inositol 1 4 5-Trisphosphate Biology Cholangiocyte Antibodies chemistry.chemical_compound Internal medicine medicine Animals Phosphorylation Autocrine signalling Ligation Protein kinase C Cells Cultured Cell Proliferation Hepatology Gastroenterology Vascular Endothelial Growth Factor Receptor-3 Vascular Endothelial Growth Factor Receptor-2 Rats Inbred F344 Recombinant Proteins Cell biology Rats Recombinant Vascular Endothelial Growth Factor Vascular endothelial growth factor Autocrine Communication Endocrinology src-Family Kinases chemistry Hepatocytes Calcium Bile Ducts Signal transduction Mitogen-Activated Protein Kinases Proto-oncogene tyrosine-protein kinase Src |
| Popis: | Background & Aims: Vascular endothelial growth factor (VEGF) is secreted by several epithelia and modulates cellular functions by autocrine and paracrine mechanisms. The role of VEGF in cholangiocyte pathophysiology is unknown. We evaluated the role of VEGF in the regulation of cholangiocyte proliferation in rats that underwent bile duct ligation. Methods: The expression of VEGF-A and VEGF-C and their receptors in cholangiocytes from normal and BDL rats was evaluated. Normal or BDL rats were treated with recombinant-VEGF-A or recombinant-VEGF-C or anti-VEGF antibodies, and proliferation of cholangiocytes was evaluated in situ by morphometry and in vitro by proliferating cell nuclear antigen immunoblots and MTS assay. In vitro, normal rat cholangiocyte cultures were stimulated with r-VEGF-A or r-VEGF-C and proliferation and signal transduction were evaluated. Results: We found that (1) cholangiocytes express messenger RNA and protein for VEGF-A, VEGF-C, VEGF receptor 2 (VEGFR-2), and VEGF receptor 3 (VEGFR-3) and secrete VEGF; (2) secretion of VEGF and expression of VEGFR-2 and VEGFR-3 increases in BDL cholangiocytes; (3) blocking VEGF in vivo by anti–VEGF-A or anti–VEGF-C antibodies decreases cholangiocyte proliferation; (4) the in vivo administration of r-VEGF-A or r-VEGF-C induces cholangiocyte proliferation in normal rats; and (5) in vitro, VEGF-A increases normal rat cholangiocyte culture proliferation by activation of inositol 1,4,5-triphosphate/Ca 2+ /protein kinase C α and phosphorylation of Src/ERK1/2. Conclusions: Cholangiocytes secrete VEGF and express VEGFR-2 and VEGFR-3, all of which are amplified in BDL cholangiocytes. VEGF induces cholangiocyte proliferation by activation of inositol 1,4,5-triphosphate/[Ca 2+ ] i /protein kinase C α and phosphorylation of Src/ERK1/2. VEGF mediates the adaptive proliferative response of cholangiocytes to cholestasis. |
| Databáze: | OpenAIRE |
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