Polyunsaturated fatty acid balance modulates microglial state in a murine model of oxygen-induced neovascularization

Polyunsaturated fatty acid balance modulates microglial state in a murine model of oxygen-induced neovascularization | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Polyunsaturated fatty acid balance modulates microglial state in a murine model of oxygen-induced neovascularization Esther S. Kim, Meng-Chin Lin, Cheng-Hsiang Lu, David Casero, Brian Aguirre, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7491382/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract The Oxygen-Induced Retinopathy (OIR) model is a widely used research tool to study pathological retinal neoangiogenesis observed in the development of diseases like retinopathy of prematurity (ROP) and proliferative diabetic retinopathy. While many factors are known to modulate susceptibility to OIR development, less is understood about how nutritional factors such as dietary fatty acids affect disease progression. The retina is enriched in polyunsaturated fatty acids (PUFAs) which are indispensable for normal vision, and recent work has shown that dietary supplementation of \(\:{\omega\:}\) -6-and \(\:{\omega\:}\) -3-polyunsaturated fatty acids (PUFAs) can provide a protective role against the pathological neovascularization observed in ROP. In the current study, we interrogated the effects of endogenous \(\:{\omega\:}\) -3-PUFA enrichment using transgenic fat-1 mice which converts \(\:{\omega\:}\) -6-PUFAs to \(\:{\omega\:}\) -3-PUFAs. These animals develop features of ROP but show attenuation in retinopathy development. Using a combination of immunofluorescence and whole retinal RNA sequencing, genes associated with angiogenesis, inflammation, and microglial activation were upregulated in WT OIR vs. WT RA (room air), with little or no change found in fat-1 OIR vs. fat-1 RA. In addition, Fat-1 mice demonstrated differential enrichment of microglial subtypes in response to OIR. This finding suggests that decreased \(\:{\omega\:}\) -6: \(\:{\omega\:}\) -3 protects against neovascularization by attenuating hyperoxia-induced microglial activation. Biological sciences/Cell biology Health sciences/Diseases Health sciences/Medical research retina retinopathy of prematurity oxygen-induced retinopathy polyunsaturated fatty acids angiogenesis hypoxia microglia Full Text Additional Declarations Competing interest reported. K.L.C. serves as an advisor for Fresenius Kabi and Baxter and serves as a principal investigator, with no salary funding, for a consortium database sponsored by Reckitt/Mead Johnson Nutrition. C.R.M. serves on the scientific advisory boards of LactaLogics, Inc., Plakous Therapeutics, and Vitara Biomedical, Inc. C.R.M. receives research funding from Reckitt/Mead Johnson Nutrition. E.K, M.C.L, C.L, D.C, B.A, J.B, O.O, M.W., A.C. do not have competing interests or other interests that might be perceived to influence the paper. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7491382","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":516588169,"identity":"1230b7bf-5155-4a76-a976-5d4cd7b405b4","order_by":0,"name":"Esther S. 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K.L.C. serves as an advisor for Fresenius Kabi and Baxter and serves as a principal investigator, with no salary funding, for a consortium database sponsored by Reckitt/Mead Johnson Nutrition. C.R.M. serves on the scientific advisory boards of LactaLogics, Inc., Plakous Therapeutics, and Vitara Biomedical, Inc. C.R.M. receives research funding from Reckitt/Mead Johnson Nutrition. E.K, M.C.L, C.L, D.C, B.A, J.B, O.O, M.W., A.C. do not have competing interests or other interests that might be perceived to influence the paper.","formattedTitle":"Polyunsaturated fatty acid balance modulates microglial state in a murine model of oxygen-induced neovascularization","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"retina, retinopathy of prematurity, oxygen-induced retinopathy, polyunsaturated fatty acids, angiogenesis, hypoxia, microglia","lastPublishedDoi":"10.21203/rs.3.rs-7491382/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7491382/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe Oxygen-Induced Retinopathy (OIR) model is a widely used research tool to study pathological retinal neoangiogenesis observed in the development of diseases like retinopathy of prematurity (ROP) and proliferative diabetic retinopathy. While many factors are known to modulate susceptibility to OIR development, less is understood about how nutritional factors such as dietary fatty acids affect disease progression. The retina is enriched in polyunsaturated fatty acids (PUFAs) which are indispensable for normal vision, and recent work has shown that dietary supplementation of \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{\\omega\\:}\\)\u003c/span\u003e\u003c/span\u003e-6-and \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{\\omega\\:}\\)\u003c/span\u003e\u003c/span\u003e-3-polyunsaturated fatty acids (PUFAs) can provide a protective role against the pathological neovascularization observed in ROP. In the current study, we interrogated the effects of endogenous \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{\\omega\\:}\\)\u003c/span\u003e\u003c/span\u003e-3-PUFA enrichment using transgenic \u003cem\u003efat-1\u003c/em\u003e mice which converts \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{\\omega\\:}\\)\u003c/span\u003e\u003c/span\u003e-6-PUFAs to \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{\\omega\\:}\\)\u003c/span\u003e\u003c/span\u003e-3-PUFAs. These animals develop features of ROP but show attenuation in retinopathy development. Using a combination of immunofluorescence and whole retinal RNA sequencing, genes associated with angiogenesis, inflammation, and microglial activation were upregulated in WT OIR vs. WT RA (room air), with little or no change found in \u003cem\u003efat-1\u003c/em\u003e OIR vs. \u003cem\u003efat-1\u003c/em\u003e RA. In addition, \u003cem\u003eFat-1\u003c/em\u003e mice demonstrated differential enrichment of microglial subtypes in response to OIR. This finding suggests that decreased \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{\\omega\\:}\\)\u003c/span\u003e\u003c/span\u003e-6:\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{\\omega\\:}\\)\u003c/span\u003e\u003c/span\u003e-3 protects against neovascularization by attenuating hyperoxia-induced microglial activation.\u003c/p\u003e","manuscriptTitle":"Polyunsaturated fatty acid balance modulates microglial state in a murine model of oxygen-induced neovascularization","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-23 18:03:34","doi":"10.21203/rs.3.rs-7491382/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"edddae8a-83a3-4e60-bcef-af7bf316db9d","owner":[],"postedDate":"September 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":54887774,"name":"Biological sciences/Cell biology"},{"id":54887775,"name":"Health sciences/Diseases"},{"id":54887776,"name":"Health sciences/Medical research"}],"tags":[],"updatedAt":"2025-12-20T17:54:01+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-23 18:03:34","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7491382","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7491382","identity":"rs-7491382","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}