{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T23:44:42Z","timestamp":1790207082188,"version":"4.1.0"},"reference-count":61,"publisher":"Wiley","issue":"22","license":[{"start":{"date-parts":[[2022,8,9]],"date-time":"2022-08-09T00:00:00Z","timestamp":1660003200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["P30EY031631"],"award-info":[{"award-number":["P30EY031631"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100017607","name":"Shenzhen Fundamental Research Program","doi-asserted-by":"publisher","award":["GXWD20201231165807007\u201020200818123312001"],"award-info":[{"award-number":["GXWD20201231165807007\u201020200818123312001"]}],"id":[{"id":"10.13039\/501100017607","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>Pathological angiogenesis is a major cause of irreversible blindness in individuals with neovascular age\u2010related macular degeneration (nAMD). Macrophages and microglia (M\u03a6) contribute to aberrant ocular angiogenesis. However, the role of glucose metabolism of M\u03a6 in nAMD is still undefined. Here, we have investigated the involvement of glycolysis, driven by the kinase\/phosphatase PFKFB3, in the development of choroidal neovascularization (CNV).<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>CNV was induced in mice with laser photocoagulation. Choroid\/retinal pigment epithelium (RPE) complexes and M\u03a6 were isolated for analysis by qRT\u2010PCR, western blot, flow cytometry, immunostaining, metabolic measurements and angiogenesis assays.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>M\u03a6 accumulated within the CNV of murine nAMD models and expressed high levels of glycolysis\u2010related enzymes and M1\/M2 polarization markers. This phenotype of hyper\u2010glycolytic and activated M\u03a6 was replicated in bone marrow\u2010derived macrophages stimulated by necrotic RPE in vitro. Myeloid cell\u2010specific knockout of PFKFB3, a key glycolytic activator, attenuated pathological neovascularization in laser\u2010induced CNV, which was associated with decreased expression of M\u03a6 polarization markers and pro\u2010angiogenic factors, along with decreased sprouting of vessels in choroid\/RPE complexes. Mechanistically, necrotic RPE increased PFKFB3\u2010driven glycolysis in macrophages, leading to activation of HIF\u20101\u03b1\/HIF\u20102\u03b1 and NF\u2010\u03baB, and subsequent induction of M1\/M2 markers and pro\u2010angiogenic cytokines, finally promoting macrophage reprogramming towards an angiogenic phenotype to facilitate development of CNV. The PFKFB3 inhibitor AZ67 also inhibited activation of HIF\u20101\u03b1\/HIF\u20102\u03b1 and NF\u2010\u03baB signalling and almost completely prevented laser\u2010induced CNV in mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Modulation of PFKFB3\u2010mediated macrophage glycolysis and activation is a promising strategy for the treatment of nAMD.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15925","type":"journal-article","created":{"date-parts":[[2022,7,13]],"date-time":"2022-07-13T16:32:52Z","timestamp":1657729972000},"page":"5109-5131","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["Suppression of myeloid PFKFB3\u2010driven glycolysis protects mice from choroidal 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