Cited by 246Retinal Diseases and TreatmentsOcular Diseases and Behçet’s SyndromeBarrier Structure and Function Studies

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Corticosteroids inhibit VEGF-induced vascular leakage in a rabbit model of blood–retinal and blood–aqueous barrier breakdown

Edelman, Jeffrey L., Lutz, David, Castro, Marisol R.·2005·Experimental Eye Research

DOI 10.1016/j.exer.2004.09.013

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Purpose Recent clinical studies show that a single intravitreal injection of the corticosteroid triamcinolone acetonide (TAA) may reduce edematous retinal swelling and improve visual acuity in patients with diabetic macular edema (DME). In addition, clinical and experimental studies strongly suggest that blood-retinal barrier breakdown in diabetes is induced by vascular endothelial growth factor (VEGF). These results suggest that corticosteroids may modulate VEGF-mediated responses in vivo. To test this hypothesis directly, the current study evaluated the effects of TAA and dexamethasone (DEX) in a newly developed rabbit model of VEGF-induced blood-retinal barrier and blood-aqueous (iris) barrier breakdown.Methods VEGF165 or vehicle was injected intravitreally in female Dutch Belt rabbits, and scanning ocular fluorophotometry was used to non-invasively measure fluorescein leakage from retinal and iris vasculature. VEGF-induced retinal vasculopathy was further assessed with fundus imaging, fluorescein angiography, and ocular coherence tomography. For pharmacologic studies, rabbits were treated with either DEX (2 mg kg(-1) daily, s.c.), TAA (2 or 4 mg, intravitreal), indomethacin (20 mg kg(-1) daily, s.c.), or vehicle (s.c. or intravitreal). Human umbilical vein endothelial cells (HUVEC) were loaded with the fluorescent Ca2+ indicator dye fluo-4 and treated with dexamethasone (0.1-10 microM) or vehicle for either 2 or 24 hr prior to stimulation with 10 ng ml(-1) VEGF165.Results VEGF injected intravitreally induced a time and dose-dependent breakdown of the blood-retinal and blood-aqueous barriers. Maximal vascular leakage was measured at 48 hr after intravitreal injection with a dose of 500 ng VEGF. Other effects of VEGF included prominent retinal vasodilation, vessel tortuousity, fluorescein leakage from retinal vessels, and inner retinal edema. These VEGF-mediated responses are transient and approach baseline by 1 week. VEGF-induced blood-retinal and blood-aqueous barrier breakdown was completely blocked by the corticosteroid DEX administered systemically for 3 days. In contrast, the non-steroidal anti-inflammatory drug, indomethacin, had no effect. In a separate study with VEGF injected intravitreally at six different time points over 5 months, a single intravitreal 2 mg dose of TAA completely blocked VEGF-induced retinal and iris leakage for 45 days. VEGF/VEGF receptor-2-mediated Ca2+ mobilization in endothelial cells was not affected by 2 or 24 hr pretreatment with dexamethasone.Conclusion These results indicate that one mechanism by which corticosteroids block blood-ocular barrier breakdown and edema is via their modulation of signaling or effector proteins downstream of the VEGF receptor.

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Authors: Edelman, J. L., Lutz, D., & Castro, M. R.
Affiliations: Allergan (United States) (US)
Corresponding author: Edelman, Jeffrey L.
Venue: Experimental Eye Research
Publisher: Elsevier BV
Published: 2005-02
Volume: 80
Issue: 2
Pages: 249-258
ISSN: 0014-4835 (ISSN-L)
DOI: 10.1016/j.exer.2004.09.013
OpenAlex: W2027693928
Cited by: 246
References: 42
Citations by year: 2026: 4 · 2025: 2 · 2024: 4 · 2023: 3 · 2022: 14 · 2021: 7 · 2020: 6 · 2019: 11 · 2018: 13 · 2017: 15 · 2016: 12 · 2015: 14 · 2014: 12 · 2013: 14 · 2012: 18
FWCI: 10.49
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Experimental Eye Research (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
Health Sciences › Medicine › Ophthalmology › Ocular Diseases and Behçet’s Syndrome
Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Keywords: corticosteroids, dexamethasone, triamcinolone acetonide, VEGF165, vascular leakage, blood-retinal barrier breakdown, blood-aqueous barrier breakdown, diabetic macular edema, retinal vascular disease, indomethacin, nonsteroidal anti-inflammatory drugs, endothelial calcium signaling, rabbit model, intravitreal injection
MeSH terms: Animals, Anti-Inflammatory Agents, Blood-Retinal Barrier, Calcium, Dexamethasone, Dose-Response Relationship, Drug, Endothelium, Vascular, Female, Fluorescein Angiography, Fundus Oculi, Glucocorticoids, Macular Edema, Rabbits, Recombinant Proteins, Triamcinolone Acetonide, Blood-Aqueous Barrier, Tomography, Optical Coherence, Vascular Endothelial Growth Factor A

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Corticosteroids inhibit VEGF-induced vascular leakage in a rabbit model of blood–retinal and blood–aqueous barrier breakdown

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