Endothelial-specific postnatal deletion of Nos3 preserves intraocular pressure homeostasis via macrophage recruitment and NOS2 upregulation

Ruth A. Kelly; Megan S. Kuhn; Ester Reina-Torres; Revathi Balasubramanian; Kristin M. Perkumas; Guorong Li; Takamune Takahashi; Simon W.M. John; Michael H. Elliott; Darryl R. Overby; W. Daniel Stamer

doi:10.1172/JCI183440

¹Department of Ophthalmology, Duke Eye Center, Duke University, Durham, United States of America

²Deparment of Bioengineering, Imperial College London, London, United Kingdom

³Department of Ophthalmology, Columbia University, New York, United States of America

⁴Division of Nephrology and Hypertension, Vanderbilt University, Nashville, United States of America

⁵Department of Ophthalmology, Dean McGee Eye Institute University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

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¹Department of Ophthalmology, Duke Eye Center, Duke University, Durham, United States of America

²Deparment of Bioengineering, Imperial College London, London, United Kingdom

³Department of Ophthalmology, Columbia University, New York, United States of America

⁴Division of Nephrology and Hypertension, Vanderbilt University, Nashville, United States of America

⁵Department of Ophthalmology, Dean McGee Eye Institute University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

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¹Department of Ophthalmology, Duke Eye Center, Duke University, Durham, United States of America

²Deparment of Bioengineering, Imperial College London, London, United Kingdom

³Department of Ophthalmology, Columbia University, New York, United States of America

⁴Division of Nephrology and Hypertension, Vanderbilt University, Nashville, United States of America

⁵Department of Ophthalmology, Dean McGee Eye Institute University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

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¹Department of Ophthalmology, Duke Eye Center, Duke University, Durham, United States of America

²Deparment of Bioengineering, Imperial College London, London, United Kingdom

³Department of Ophthalmology, Columbia University, New York, United States of America

⁴Division of Nephrology and Hypertension, Vanderbilt University, Nashville, United States of America

⁵Department of Ophthalmology, Dean McGee Eye Institute University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

Find articles by Balasubramanian, R. in: JCI | PubMed | Google Scholar

¹Department of Ophthalmology, Duke Eye Center, Duke University, Durham, United States of America

²Deparment of Bioengineering, Imperial College London, London, United Kingdom

³Department of Ophthalmology, Columbia University, New York, United States of America

⁴Division of Nephrology and Hypertension, Vanderbilt University, Nashville, United States of America

⁵Department of Ophthalmology, Dean McGee Eye Institute University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

Find articles by Perkumas, K. in: JCI | PubMed | Google Scholar

¹Department of Ophthalmology, Duke Eye Center, Duke University, Durham, United States of America

²Deparment of Bioengineering, Imperial College London, London, United Kingdom

³Department of Ophthalmology, Columbia University, New York, United States of America

⁴Division of Nephrology and Hypertension, Vanderbilt University, Nashville, United States of America

⁵Department of Ophthalmology, Dean McGee Eye Institute University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

Find articles by Li, G. in: JCI | PubMed | Google Scholar

¹Department of Ophthalmology, Duke Eye Center, Duke University, Durham, United States of America

²Deparment of Bioengineering, Imperial College London, London, United Kingdom

³Department of Ophthalmology, Columbia University, New York, United States of America

⁴Division of Nephrology and Hypertension, Vanderbilt University, Nashville, United States of America

⁵Department of Ophthalmology, Dean McGee Eye Institute University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

Find articles by Takahashi, T. in: JCI | PubMed | Google Scholar

¹Department of Ophthalmology, Duke Eye Center, Duke University, Durham, United States of America

²Deparment of Bioengineering, Imperial College London, London, United Kingdom

³Department of Ophthalmology, Columbia University, New York, United States of America

⁴Division of Nephrology and Hypertension, Vanderbilt University, Nashville, United States of America

⁵Department of Ophthalmology, Dean McGee Eye Institute University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

Find articles by John, S. in: JCI | PubMed | Google Scholar

¹Department of Ophthalmology, Duke Eye Center, Duke University, Durham, United States of America

²Deparment of Bioengineering, Imperial College London, London, United Kingdom

³Department of Ophthalmology, Columbia University, New York, United States of America

⁴Division of Nephrology and Hypertension, Vanderbilt University, Nashville, United States of America

⁵Department of Ophthalmology, Dean McGee Eye Institute University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

Find articles by Elliott, M. in: JCI | PubMed | Google Scholar

¹Department of Ophthalmology, Duke Eye Center, Duke University, Durham, United States of America

²Deparment of Bioengineering, Imperial College London, London, United Kingdom

³Department of Ophthalmology, Columbia University, New York, United States of America

⁴Division of Nephrology and Hypertension, Vanderbilt University, Nashville, United States of America

⁵Department of Ophthalmology, Dean McGee Eye Institute University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

Find articles by Overby, D. in: JCI | PubMed | Google Scholar |

¹Department of Ophthalmology, Duke Eye Center, Duke University, Durham, United States of America

²Deparment of Bioengineering, Imperial College London, London, United Kingdom

³Department of Ophthalmology, Columbia University, New York, United States of America

⁴Division of Nephrology and Hypertension, Vanderbilt University, Nashville, United States of America

⁵Department of Ophthalmology, Dean McGee Eye Institute University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

Find articles by Stamer, W. in: JCI | PubMed | Google Scholar

J Clin Invest. https://doi.org/10.1172/JCI183440.
Copyright © 2025, Kelly et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published February 11, 2025 - Version history

Polymorphisms in Nos3 increases risk for glaucoma, the leading cause of irreversible blindness worldwide. A key modifiable risk factor for glaucoma is intraocular pressure (IOP), which is regulated by nitric oxide (NO), a product of nitric oxide synthase-3 (Nos3) in Schlemm’s canal of the conventional outflow pathway. We studied the effects of a conditional, endothelial-specific postnatal deletion of Nos3 (Endo-SclCre-ERT;Nos3^flox/flox) on tissues of the outflow pathway. We observed that Cre-ER^T expression spontaneously and gradually increased with time in vascular endothelia including Schlemm’s canal, beginning at P10, with complete Nos3 deletion occurring around P90. Unlike the reduced outflow resistance in global Nos3 knockout mice, outflow resistance and IOP in Endo-SclCre-ER^T;Nos3^flox/flox mice were normal. Coinciding with Nos3 deletion, we observed recruitment of macrophages to, and induction of both ELAM-1 and NOS2 expression by endothelia in the distal portion of the outflow pathway, which increased vessel diameter. These adjustments reduced outflow resistance to maintain IOP in these Endo-SclCre-ER^T;Nos3^flox/flox mice. Selective inhibition of iNOS by 1400W resulted in narrowing of distal vessels and IOP elevation. Together, results emphasize the pliability of the outflow system, the importance of NO signaling in IOP control and implicates an important role for macrophages in IOP homeostasis.

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Endothelial-specific postnatal deletion of Nos3 preserves intraocular pressure homeostasis via macrophage recruitment and NOS2 upregulation

Ruth A. Kelly,¹ Megan S. Kuhn,¹ Ester Reina-Torres,² Revathi Balasubramanian,³ Kristin M. Perkumas,¹ Guorong Li,¹ Takamune Takahashi,⁴ Simon W.M. John,³ Michael H. Elliott,⁵ Darryl R. Overby,⁴ and W. Daniel Stamer¹

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Endothelial-specific postnatal deletion of Nos3 preserves intraocular pressure homeostasis via macrophage recruitment and NOS2 upregulation

Ruth A. Kelly,1 Megan S. Kuhn,1 Ester Reina-Torres,2 Revathi Balasubramanian,3 Kristin M. Perkumas,1 Guorong Li,1 Takamune Takahashi,4 Simon W.M. John,3 Michael H. Elliott,5 Darryl R. Overby,4 and W. Daniel Stamer1

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Ruth A. Kelly,¹ Megan S. Kuhn,¹ Ester Reina-Torres,² Revathi Balasubramanian,³ Kristin M. Perkumas,¹ Guorong Li,¹ Takamune Takahashi,⁴ Simon W.M. John,³ Michael H. Elliott,⁵ Darryl R. Overby,⁴ and W. Daniel Stamer¹