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IOP remains within a narrow range despite age-associated changes predicted to increase aqueous humor outflow (AHO) resistance at the interface between the trabecular meshwork and Schlemm\u2019s canal (SC), suggesting compensatory mechanisms preserve AHO homeostasis during aging. Single-cell RNA sequencing of mouse ocular angle tissues revealed immunomodulatory transcriptional reprogramming of SC endothelial cells in older mice, while mouse and human imaging showed reduced SC size and increased peri-SC macrophage accumulation with aging. Ligand\u2013receptor analysis predicted enhanced macrophage-to-SC VEGFA\u2013VEGFR signaling in aged and\n                  <jats:italic>Tie2<\/jats:italic>\n                  -haploinsufficient mice, an independent model of vascular stress and glaucoma risk. Deletion of\n                  <jats:italic>Vegfa<\/jats:italic>\n                  in CX3CR1\n                  <jats:sup>+<\/jats:sup>\n                  macrophages increased IOP and reduced AHO facility in 9-month-old mice, demonstrating that macrophage-derived VEGFA supports AHO homeostasis.\n                  <jats:italic>Tie2<\/jats:italic>\n                  haploinsufficiency recapitulated key age-associated SC niche changes, including peri-SC macrophage accumulation, whereas gene therapy boosting TIE2 activity protected wild-type mice against age-related changes. Together, these findings identify peri-SC macrophage-derived VEGFA as a compensatory mechanism maintaining AHO homeostasis during aging and vascular stress and support TIE2 activation as a therapeutic strategy to preserve SC function and IOP regulation.\n                <\/jats:p>","DOI":"10.64898\/2026.08.20.746006","type":"posted-content","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T04:55:17Z","timestamp":1787633717000},"source":"Crossref","is-referenced-by-count":0,"title":["VEGFA-Positive Macrophages Regulate Aqueous Humor Outflow in Aged Mice and Humans"],"prefix":"10.64898","author":[{"given":"Naoki","family":"Kiyota","sequence":"first","affiliation":[{"name":"Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago"},{"name":"Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yalu","family":"Zhou","sequence":"additional","affiliation":[{"name":"Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago"},{"name":"Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dilip K.","family":"Deb","sequence":"additional","affiliation":[{"name":"Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago"},{"name":"Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guohui","family":"Ren","sequence":"additional","affiliation":[{"name":"Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago"},{"name":"Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuncer","family":"Onay","sequence":"additional","affiliation":[{"name":"Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago"},{"name":"Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ester","family":"Reina-Torres","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, Imperial College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hoi-Lam","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Department of Anatomy and Neurobiology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constance E.","family":"Runyan","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert S.","family":"Feder","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Northwestern University Feinberg School of Medicine, Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyunjoo J.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Harvard Medical School, and Massachusetts Eye and Ear, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darryl R.","family":"Overby","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, Imperial College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyan","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Department of Anatomy and Neurobiology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G. 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