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This study examined the effects of palmitic acid (PA) exposure, alone and combined with high glucose (G25), on M\u00fcller Glial Cell (MGC) dysfunction and angiogenic signaling. Primary MGC cultures were treated with G25 (25 mM), PA (250 \u00b5M), or PA + G25 for 24 and 48 h, followed by assessments of cell viability and analysis of the Vascular Endothelial Growth Factor (VEGFA)\/VEGFA receptor 2 (VEGFR2) pathway through immunofluorescence, Western blot, and ELISA. Additionally, Gaussian mixture models (GMMs) were used to identify phenotypic subpopulations based on fluorescence intensity. The results showed that while hyperglycemia did not cause significant changes, PA and PA + G25 induced apoptosis-related cell death and significantly increased the expression of VEGFA, VEGFR2, HIF-\u03b1, and SP1. Although broad phenotypic diversity was observed at 24 h, by 48 h, a distinct shift towards an angiogenic phenotype was noted, with significantly elevated VEGFA\/VEGFR2 levels. In summary, this research demonstrates that PA acts as a critical inducer of an angiogenic secretory phenotype in MGCs, indicating that lipid-mediated signaling plays a vital role in neovascularization in DR, possibly independent of glucose levels.<\/jats:p>","DOI":"10.3390\/ijms27115144","type":"journal-article","created":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T17:18:16Z","timestamp":1780679896000},"page":"5144","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Beyond Glucose: Palmitic Acid Influences VEGFA-VEGFR2 Angiogenic Signaling in M\u00fcller Glial Cells"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9867-430X","authenticated-orcid":false,"given":"Jesus Silvestre","family":"Albert-Garay","sequence":"first","affiliation":[{"name":"Laboratorio de Neurobiolog\u00eda Molecular y Celular de la Gl\u00eda, Departamento de Bioqu\u00edmica, Facultad de Medicina, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Mexico City C.P. 04510, Mexico"},{"name":"Unidad de Investigaci\u00f3n, Asociaci\u00f3n Para Evitar la Ceguera en M\u00e9xico I.A.P., Mexico City C.P. 04030, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4139-7900","authenticated-orcid":false,"given":"Alan E.","family":"Medina Arellano","sequence":"additional","affiliation":[{"name":"Laboratorio de Neurobiolog\u00eda Molecular y Celular de la Gl\u00eda, Departamento de Bioqu\u00edmica, Facultad de Medicina, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Mexico City C.P. 04510, Mexico"},{"name":"Unidad de Investigaci\u00f3n, Asociaci\u00f3n Para Evitar la Ceguera en M\u00e9xico I.A.P., Mexico City C.P. 04030, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5932-8911","authenticated-orcid":false,"given":"Karla","family":"Hern\u00e1ndez-Fonseca","sequence":"additional","affiliation":[{"name":"Laboratorio de Neuroqu\u00edmica, Subdirecci\u00f3n de Investigaciones Cl\u00ednicas, Instituto Nacional de Psiquiatr\u00eda \u201cRam\u00f3n de la Fuente Mu\u00f1iz\u201d, Mexico City C.P. 14370, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tania","family":"Medina-S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Laboratorio de Neuroqu\u00edmica, Subdirecci\u00f3n de Investigaciones Cl\u00ednicas, Instituto Nacional de Psiquiatr\u00eda \u201cRam\u00f3n de la Fuente Mu\u00f1iz\u201d, Mexico City C.P. 14370, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7293-0739","authenticated-orcid":false,"given":"Matilde","family":"Ruiz-Cruz","sequence":"additional","affiliation":[{"name":"Unidad de Investigaci\u00f3n, Asociaci\u00f3n Para Evitar la Ceguera en M\u00e9xico I.A.P., Mexico City C.P. 04030, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7561-0853","authenticated-orcid":false,"given":"Lenin","family":"Ochoa-de la Paz","sequence":"additional","affiliation":[{"name":"Laboratorio de Neurobiolog\u00eda Molecular y Celular de la Gl\u00eda, Departamento de Bioqu\u00edmica, Facultad de Medicina, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Mexico City C.P. 04510, Mexico"},{"name":"Unidad de Investigaci\u00f3n, Asociaci\u00f3n Para Evitar la Ceguera en M\u00e9xico I.A.P., Mexico City C.P. 04030, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,5]]},"reference":[{"key":"ref_1","unstructured":"International Diabetes Federation (2025). 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