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J.L. Edelman, D. Lutz; Reversible Blood-Retinal Barrier (BRB) and Blood Aqueous-Barrier (BAB) Breakdown After a Single Intravitreal Injection of rhVEGF-165 . Invest. Ophthalmol. Vis. Sci. 2003;44(13):328.
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Purpose. Retinal ischemia markedly upregulates the expression of the multifunctional protein vascular endothelial growth factor (VEGF). As a potent vascular permeability factor, VEGF may induce local extravasation and edema, or alternatively, it may diffuse from retina to vitreous and alter blood-ocular barriers at distant sites. The current goals were 1) to determine if a single intravitreal VEGF injection induces BRB or BAB breakdown, and 2) to elucidate the signaling mechanisms underlying these effects. Methods. Recombinant human VEGF165 (rhVEGF165) or vehicle was injected intra-vitreally in female Dutch Belt rabbits. At 6 hrs to 7 days after injection, ocular Na fluorescein leakage was measured by fluorophotometry. For pharmacology studies, rabbits either received vehicle, intravitreal soluble rhVEGFR-1/Fc receptor, indomethacin (s. c., 20 mg/kg/day), or L-NAME (100 µg/ml drinking water). Results. Intravitreal rhVEGF165 caused a time-dependent breakdown of the blood-ocular barriers. Six hours after injection, a VEGF effect was obscured by a local inflammatory response. This non-specific leakage subsided by 24 hrs, and at this time VEGF significantly increased vitreal and aqueous chamber leakage. The extent of vascular leakage peaked by day 2 and returned to near normal by day 7. The response to intravitreal VEGF was also dose-dependent: 50 ng caused mild BRB breakdown, 200 ng caused moderate BRB breakdown and mild BAB breakdown, and 500 ng caused intense BRB and BAB breakdown. The extent of rhVEGF165-induced BRB breakdown was not altered by indomethacin or L-NAME, however, BRB breakdown was completely blocked with intravitreal rhVEGF-R1/Fc receptor. Conclusions. A single intravitreal injection of rhVEGF165 caused a time and dose-dependent breakdown of the blood-retinal and blood-aqueous barriers. The signaling pathway underlying VEGF-induced vascular leakage is poorly understood, however, it does not appear to require cyclo-oxygenase or nitric-oxide synthase. CR: E.
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