ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Inflammation Pharmacology
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1608376
This article is part of the Research TopicPUFA Lipid Mediators in Inflammation and Associated Chronic Ocular and Neurological DiseasesView all articles
Prostaglandin E2 stimulates opposing effects on inner and outer blood-retina barrier function
Provisionally accepted
- 1Department of Pharmacology, School of Medicine, Vanderbilt University, Nashville, Tennessee, United States
- 2Department of Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, United States
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Diabetic retinopathy (DR) is the leading cause of vision loss in working-age individuals globally, and the associated complication of diabetic macular edema (DME) is the most frequent cause of vision loss in these patients. The retinal swelling characteristic of DME can be attributed to fluid leakage due to damage to the two blood-retina barriers—the inner barrier composed primarily of retinal microvascular endothelial cells and the outer barrier composed of retinal pigment epithelial cells (RPE). Based on the previously characterized proinflammatory roles of prostanoid signaling in DR, we assayed the distinct prostanoid signaling mechanisms regulating inner and outer blood-retina barrier function using in vitro methods involving monoculture of primary human cells. Prostaglandin E2 (PGE2) stimulation of retinal endothelial monolayers caused a decrease in barrier permeability in electric cell-substrate impedance sensing (ECIS) assays and dextran flux assays. These effects occurred via the EP4 receptor of PGE2. In direct contrast, PGE2 stimulation of RPE monolayers caused an increase in barrier permeability via the EP2 receptor. Other prostanoids did not alter barrier permeability in either monocellular model. RNA sequencing of retinal endothelial and RPE cells with or without PGE2 stimulation revealed significant dysregulation of genes encoding junctional complex components and signaling that likely drive the observed effects on cell barrier resistance. Together these results suggest opposing mechanisms of PGE2 signaling in the retina via two distinct receptors, indicating cell type-specific and likely receptor-specific targets for the potential therapeutic management of DME or other causes of dysfunctional retinal vascular permeability.
Keywords: prostaglandin, lipid signaling, Ophthalmology, Diabetic Retinopathy, blood-retina barrier, Barrier function, Inflammation, diabetic macular edema
Received: 08 Apr 2025; Accepted: 31 Aug 2025.
Copyright: © 2025 Stark and Penn. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Amy Kathryn Stark, Department of Pharmacology, School of Medicine, Vanderbilt University, Nashville, 37240-7933, Tennessee, United States
John Sidney Penn, Department of Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, 37232, Tennessee, United States
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