{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T23:55:00Z","timestamp":1789430100585,"version":"build-2803163510"},"reference-count":91,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T00:00:00Z","timestamp":1772064000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000053","name":"UCLA Children\u2019s Discovery and Innovation Institute NIH NEI","doi-asserted-by":"publisher","award":["T32 EY007026"],"award-info":[{"award-number":["T32 EY007026"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000053","name":"UCLA Children\u2019s Discovery and Innovation Institute NIH NEI","doi-asserted-by":"publisher","award":["R01 EY032561"],"award-info":[{"award-number":["R01 EY032561"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"name":"UCLA DGSOM Seed Grant NIH NCATS","award":["UL1TR001881"],"award-info":[{"award-number":["UL1TR001881"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background\/Objectives: The retina is enriched in polyunsaturated fatty acids (PUFAs) which are indispensable for normal vision, and recent clinical studies have shown that dietary supplementation of \u03c9-6-and \u03c9-3-polyunsaturated fatty acids (PUFAs) can provide a protective role against retinopathy of prematurity (ROP). Our study aims to understand the mechanisms by which altering \u03c9-6-and \u03c9-3-polyunsaturated fatty acids (PUFAs) in the eye can protect against pathologic retinal neovascularization (NV). Methods: We interrogated the effects of endogenous \u03c9-3-PUFA enrichment using transgenic fat-1 mice which convert \u03c9-6-PUFAs to \u03c9-3-PUFAs in the oxygen-induced retinopathy (OIR) murine model. In the OIR model, mice are exposed to 75% oxygen from postnatal day 7 (P7) to P12, then returned to room air (RA). We used a combination of immunofluorescence, bulk retinal RNA sequencing, and lipid mediator profiling by UHPLC-MS\/MS in P17 mouse retinas to identify mechanisms underlying the protective effect against NV seen in fat-1 mice exposed to OIR. Results:Fat-1 OIR mice were protected against the development of retinopathy, demonstrating 15.1% less vaso-obliteration (75.5% relative reduction) after OIR and a 6.1% reduction in neovascularization (71.8% relative reduction) at P17 (p &lt; 0.0001 for both). We found a dampened transcriptional response to OIR in the retina of fat-1 mice as compared to WT mouse retinas (198 vs. 782 genes, adjusted p-value &lt; 0.01). Pathway analyses confirmed these findings, with significant OIR-induced transcriptional shifts in angiogenesis (adjusted p-value &lt; 10\u221227), inflammation (adjusted p-value &lt; 10\u221225), and microglial activation pathways (adjusted p-value &lt; 10\u22129) in WT mouse retina that were not observed in fat-1 mice. Enrichment scores obtained through the integration of our bulk transcriptomics data with cell-resolved retina data indicate that the protective phenotype observed in fat-1 mice could be associated with intrinsic differences in microglia cell subtypes between WT and fat-1 mice. In situ, WT OIR mice demonstrated an increase in Iba1+ microglia compared to WT RA mice, whereas fat-1 OIR mice showed no difference when compared to fat-1 RA mice. Three ARA-derived oxylipins, 12-hydroxyeicosatetraenoic acid (12-HETE), prostaglandin D2 (PGD2), and thromboxane B2 (TXB2) demonstrated a pattern of upregulation in WT OIR compared to WT RA, but no upregulation in fat-1 OIR mice compared to fat-1 RA. Two EPA-derived specialized pro-resolving mediators and two LA-derived oxylipins were also differentially expressed. Conclusions: These findings show that a lower \u03c9-6:\u03c9-3 protects against neovascularization and is associated with attenuation of hyperoxia-induced microglial recruitment and activation, as well as inflammation and angiogenic signaling.<\/jats:p>","DOI":"10.3390\/nu18050749","type":"journal-article","created":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T13:58:03Z","timestamp":1772114283000},"page":"749","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Polyunsaturated Fatty Acid Balance Modulates Microglial State in a Murine Model of Oxygen-Induced Neovascularization"],"prefix":"10.3390","volume":"18","author":[{"given":"Esther S.","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Olive View-UCLA Medical Center, 14445 Olive View Drive, Sylmar, CA 91342, USA"},{"name":"Division of Neonatology and Developmental Biology, Department of Pediatrics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng-Chin","family":"Lin","sequence":"additional","affiliation":[{"name":"Division of Neonatology and Developmental Biology, Department of Pediatrics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng-Hsiang","family":"Lu","sequence":"additional","affiliation":[{"name":"F. Widjaja Inflammatory Bowel Disease Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7347-3330","authenticated-orcid":false,"given":"David","family":"Casero","sequence":"additional","affiliation":[{"name":"F. Widjaja Inflammatory Bowel Disease Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Aguirre","sequence":"additional","affiliation":[{"name":"Department of Pathology Lab Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne","family":"Brown","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olawande","family":"Olagoke","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilia R.","family":"Martin","sequence":"additional","affiliation":[{"name":"Division of Neonatology, Department of Pediatrics, Weill Cornell Medicine, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8514-2021","authenticated-orcid":false,"given":"Madhuri","family":"Wadehra","sequence":"additional","affiliation":[{"name":"Department of Pathology Lab Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA 90095, USA"},{"name":"Jonsson Comprehensive Cancer Center, University of California-Los Angeles, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kara L.","family":"Calkins","sequence":"additional","affiliation":[{"name":"Division of Neonatology and Developmental Biology, Department of Pediatrics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1324-1439","authenticated-orcid":false,"given":"Alison","family":"Chu","sequence":"additional","affiliation":[{"name":"Division of Neonatology and Developmental Biology, Department of Pediatrics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2515","DOI":"10.1056\/NEJMra1208129","article-title":"Mechanisms and management of retinopathy of prematurity","volume":"367","author":"Hartnett","year":"2012","journal-title":"N. 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