VEGFA-Positive Macrophages Regulate Aqueous Humor Outflow in Aged Mice and Humans
- 1Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago.
Abstract
Elevated intraocular pressure (IOP) and aging are major risk factors for primary open-angle glaucoma (POAG), but how aging affects IOP regulation remains poorly understood. 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's 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-receptor analysis predicted enhanced macrophage-to-SC VEGFA-VEGFR signaling in aged and Tie2-haploinsufficient mice, an independent model of vascular stress and glaucoma risk. Deletion of Vegfa in CX3CR1+ macrophages increased IOP and reduced AHO facility in 9-month-old mice, demonstrating that macrophage-derived VEGFA supports AHO homeostasis. Tie2 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.
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BibTeX
@misc{kiyota2026vegfapositive,
title = {{VEGFA-Positive Macrophages Regulate Aqueous Humor Outflow in Aged Mice and Humans}},
author = {N. Kiyota and Y. Zhou and D. K. Deb and G. Ren and T. Onay and E. Reina-Torres and H.-L. Li and C. E. Runyan and R. S. Feder and H. J. Lee and D. R. Overby and H. Gong and G. R. S. Budinger and B. R. Thomson and S. E. Quaggin},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.20.746006},
url = {https://www.biorxiv.org/content/10.64898/2026.08.20.746006v2},
note = {CC BY},
}
RIS
TY - UNPB
TI - VEGFA-Positive Macrophages Regulate Aqueous Humor Outflow in Aged Mice and Humans
AU - N. Kiyota
AU - Y. Zhou
AU - D. K. Deb
AU - G. Ren
AU - T. Onay
AU - E. Reina-Torres
AU - H.-L. Li
AU - C. E. Runyan
AU - R. S. Feder
AU - H. J. Lee
AU - D. R. Overby
AU - H. Gong
AU - G. R. S. Budinger
AU - B. R. Thomson
AU - S. E. Quaggin
PY - 2026
DA - 2026/08/20
PB - bioRxiv
DO - 10.64898/2026.08.20.746006
UR - https://www.biorxiv.org/content/10.64898/2026.08.20.746006v2
AB - Elevated intraocular pressure (IOP) and aging are major risk factors for primary open-angle glaucoma (POAG), but how aging affects IOP regulation remains poorly understood. 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's 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-receptor analysis predicted enhanced macrophage-to-SC VEGFA-VEGFR signaling in aged and Tie2-haploinsufficient mice, an independent model of vascular stress and glaucoma risk. Deletion of Vegfa in CX3CR1+ macrophages increased IOP and reduced AHO facility in 9-month-old mice, demonstrating that macrophage-derived VEGFA supports AHO homeostasis. Tie2 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.
ER -