title: Functional relevance of the switch of VEGF receptors/co-receptors during peritoneal dialysis-induced mesothelial to mesenchymal transition.
abstract: 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.
authors.affiliation: Centro de Biología Molecular-Severo Ochoa, CSIC-UAM, Cantoblanco, Madrid, Spain.
authors.forename: María Luisa
authors.initials: ML
authors.lastname: Pérez-Lozano
authors.forename: Pilar
authors.initials: P
authors.lastname: Sandoval
authors.forename: Angela
authors.initials: A
authors.lastname: Rynne-Vidal
authors.forename: Abelardo
authors.initials: A
authors.lastname: Aguilera
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Jiménez-Heffernan
authors.forename: Patricia
authors.initials: P
authors.lastname: Albar-Vizcaíno
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Majano
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Sánchez-Tomero
authors.forename: Rafael
authors.initials: R
authors.lastname: Selgas
authors.forename: Manuel
authors.initials: M
authors.lastname: López-Cabrera
mesh_terms: D000328:Adult; D000368:Aged; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D039942:Neuropilin-1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D009852:Omentum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010530:Peritoneal Dialysis; D061251:Primary Cell Culture; D040121:Semaphorin-3A / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; D053583:Interleukin-1beta; C108639:SEMA3A protein, human; D040121:Semaphorin-3A; D053773:Transforming Growth Factor beta1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2