{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T05:55:37Z","timestamp":1790920537339,"version":"4.1.0"},"reference-count":65,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:00:00Z","timestamp":1790899200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001648","name":"European Foundation for the Study of Diabetes","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001648","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004462","name":"Consiglio Nazionale Delle Ricerche","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004462","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The functional impairment of retinal microvascular cells is an early and central event in diabetic retinopathy (DR). Methylglyoxal (MGO), the most reactive precursor of advanced glycation end products (AGEs), has been implicated in vascular injury and neuro-retinal dysfunction. Its direct effects on retinal endothelial cells and underlying molecular mechanisms remain poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Human retinal endothelial cells (hRECs) were exposed to MGO and the effect of sublethal doses on the proangiogenic function was evaluated by migration, tube formation and pericyte recruitment assays. MGO derived AGEs were evaluated by western blot. Transcriptome and miRNome profiling were performed to identify gene expression and microRNA perturbations. Integrative\n                      <jats:italic>in silico<\/jats:italic>\n                      analyses combining RNA-Seq with ENCODE ChIP-Seq datasets were used to identify transcriptional regulators responsible for MGO-induced gene deregulation. Transcriptomic profiles were compared with independent human DR datasets, and\n                      <jats:italic>REST<\/jats:italic>\n                      was silenced by siRNAs followed by analyses of proangiogenic function.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The exposure of hRECs to MGO for 72\u00a0h is sufficient to increase protein glycation adducts, impair the migration, tube-formation and the recruitment of pericytes. Transcriptome and miRNome analyses highlight that MGO induces extensive transcriptional perturbations, related to gene expression regulation, cell cycle, cell death and vasculature development. Among the identified transcriptional regulators, Neuron-Restrictive Silencer Factor\/RE1-Silencing Transcription Factor (NRSF\/REST) emerges as a candidate mediator, with binding sites enriched in 56% of deregulated genes. NRSF\/REST expression markedly increases after 24\u00a0h of MGO treatment, suggesting it is an early event of the exposure to MGO. Protein\u2013protein interaction network analysis prioritized NRSF\/REST as a central node linking key MGO-responsive pathways. Accordingly, NRSF\/REST knockdown is associated with the reduction of\n                      <jats:italic>TP53<\/jats:italic>\n                      and\n                      <jats:italic>FOSL2<\/jats:italic>\n                      , which are induced by MGO and display NRSF binding sites and known migration-related functions. Importantly,\n                      <jats:italic>REST<\/jats:italic>\n                      silencing significantly attenuates MGO-induced defects in endothelial migration, tube formation and pericyte recruitment, supporting its contribution to both transcriptional and functional endothelial alterations induced by MGO in hRECs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings demonstrate that MGO exposure disrupts endothelial function and transcriptional homeostasis in hRECs, identifying NRSF\/REST as a contributor to MGO-induced endothelial dysfunction and supporting further investigations of the MGO\/NRSF-REST axis as a potential therapeutic target for DR.<\/jats:p>\n                  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