Functional relevance of the switch of VEGF receptors/co-receptors during peritoneal dialysis-induced mesothelial to mesenchymal transition

Vascular endothelial growth factor (VEGF) is up-regulated during mesothelial to mesenchymal transition (MMT) and has been associated with peritoneal membrane dysfunction in peritoneal dialysis (PD) patients. It has been shown that normal and malignant mesothelial cells (MCs) express VEGF receptors (...

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Bibliographic Details
Published in:PloS one 2013-04, Vol.8 (4), p.e60776-e60776
Main Authors: Pérez-Lozano, María Luisa, Sandoval, Pilar, Rynne-Vidal, Angela, Aguilera, Abelardo, Jiménez-Heffernan, José Antonio, Albar-Vizcaíno, Patricia, Majano, Pedro L, Sánchez-Tomero, José Antonio, Selgas, Rafael, López-Cabrera, Manuel
Format: Article
Language:English
Subjects:
Adult
Aged
Angiogenesis
Antibodies
Antibodies, Neutralizing - pharmacology
Autocrine signalling
Biology
Blocking antibodies
Cell cycle
Dialysis
Effluents
Epithelial Cells - drug effects
Epithelial Cells - metabolism
Epithelial Cells - pathology
Epithelial-Mesenchymal Transition
Extracellular matrix
Female
Gene Expression Regulation
Humans
IL-1β
Interleukin-1beta - pharmacology
Kidney diseases
Kinases
Ligands
Male
Medicine
Mesenchyme
Mesothelioma
Middle Aged
MMT
Movement disorders
Neurodegenerative diseases
Neuropilin
Neuropilin-1 - antagonists & inhibitors
Neuropilin-1 - genetics
Neuropilin-1 - metabolism
Omentum
Omentum - drug effects
Omentum - metabolism
Omentum - pathology
Parkinson's disease
Peritoneal Dialysis
Peritoneum
Primary Cell Culture
Receptors
Semaphorin-3A - genetics
Semaphorin-3A - metabolism
Semaphorin-3A - pharmacology
Signal Transduction
Stem cells
Transforming Growth Factor beta1 - pharmacology
Transforming growth factor-b1
Transforming growth factors
Vascular endothelial growth factor
Vascular Endothelial Growth Factor A - genetics
Vascular Endothelial Growth Factor A - metabolism
Vascular Endothelial Growth Factor A - pharmacology
Vascular Endothelial Growth Factor Receptor-1 - antagonists & inhibitors
Vascular Endothelial Growth Factor Receptor-1 - genetics
Vascular Endothelial Growth Factor Receptor-1 - metabolism
Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors
Vascular Endothelial Growth Factor Receptor-2 - genetics
Vascular Endothelial Growth Factor Receptor-2 - metabolism
Vascular endothelial growth factor receptors
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Summary:Vascular endothelial growth factor (VEGF) is up-regulated during mesothelial to mesenchymal transition (MMT) and has been associated with peritoneal membrane dysfunction in peritoneal dialysis (PD) patients. It has been shown that normal and malignant mesothelial cells (MCs) express VEGF receptors (VEGFRs) and co-receptors and that VEGF is an autocrine growth factor for mesothelioma. Hence, we evaluated the expression patterns and the functional relevance of the VEGF/VEGFRs/co-receptors axis during the mesenchymal conversion of MCs induced by peritoneal dialysis. Omentum-derived MCs treated with TGF-β1 plus IL-1β (in vitro MMT) and PD effluent-derived MCs with non-epithelioid phenotype (ex vivo MMT) showed down-regulated expression of the two main receptors Flt-1/VEGFR-1 and KDR/VEGFR-2, whereas the co-receptor neuropilin-1 (Nrp-1) was up-regulated. The expression of the Nrp-1 ligand semaphorin-3A (Sema-3A), a functional VEGF competitor, was repressed throughout the MMT process. These expression pattern changes were accompanied by a reduction of the proliferation capacity and by a parallel induction of the invasive capacity of MCs that had undergone an in vitro or ex vivo MMT. Treatment with neutralizing anti-VEGF or anti-Nrp-1 antibodies showed that these molecules played a relevant role in cellular proliferation only in naïve omentum-derived MCs. Conversely, treatment with these blocking antibodies, as well as with recombinant Sema-3A, indicated that the switched VEGF/VEGFRs/co-receptors axis drove the enhanced invasion capacity of MCs undergoing MMT. In conclusion, the expression patterns of VEGFRs and co-receptors change in MCs during MMT, which in turn would determine their behaviour in terms of proliferation and invasion in response to VEGF.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0060776