Maisto, RosaOltra, MaríaVidal Gil, LorenaMartínez Gil, NataliaSancho Pellúz, JavierDi Filippo, ClaraRossi, SettimoD´Amico, MicheleBarcia, Jorge MiguelRomero Gómez, Francisco Javier2020-01-302020-01-302019Maisto, R., Oltra, M., Vidal-Gil, L., Martínez-Gil, N., Sancho-Pellúz, J., Filippo, C. Di, … Romero, F. J. (2019). ARPE-19-derived VEGF-containing exosomes promote neovascularization in HUVEC: the role of the melanocortin receptor 5. Cell Cycle, 18(4), 413–424. https://doi.org/10.1080/15384101.2019.15687451538-41011551-4005http://hdl.handle.net/11268/8552ARPE-19 retinal pigment epithelial cells cultured in a medium containing 35 mM D-glucose led to an augmented ROS formation and release of vascular endothelial factor (VEGF)-containing exosomes compared to ARPE-19 cells cultured in a medium containing 5 mM D-glucose (standard medium). Exposing these cells to the melanocortin 5 receptor agonist (MCR5) PG-901 (10−10M), for 9 d reduced ROS generation, the number of exosomes released and their VEGF content. In contrast, incubating the cells with the melanocortin receptor MCR1 agonist BMS-470539 (10−5 M) or with the mixed MCR3/4 agonist MTII (0.30 nmol) did not produce any significant decrease in ROS levels. ARPE-19-derived VEGF-containing exosomes promoted neovascularization in human umbilical vein endothelial cells (HUVEC), an effect that was markedly reduced by PG-901 (10−10M) but not by the MCR3/4 agonist MTII (0.30 nmol) or the MCR1 agonist BMS-470539 (10−5 M). The MCR5-related action in the ARPE-19 cells was accompanied by the increased expression of two coupled factors, cytochrome p4502E1 (CYP2E1) and nuclear factor kappa b (Nf-κB). These are both involved in high glucose signalling, in ROS generation and, interestingly, were reduced by the MCR5 agonist in the ARPE-19 cells. Altogether, these data suggest that MCR5 is a modulator of the responses stimulated by glucose in ARPE-19 cells, which might possibly be translated into a modulation of the retinal pigment epithelium response to diabetes in vivo.engAttribution-NonCommercial-NoDerivatives 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/journal article10.1080/15384101.2019.1568745open accessCitologíaDiabetesBiología celularEnfermedadSistema cardiovascular