Corticosteroids Inhibit VEGF–Induced Vascular Leakage in a Novel Rabbit Model of Blood–Retinal and Blood–Aqueous Barrier Breakdown.

Abstract

Abstract: : Purpose: The potent vascular permeability factor VEGF is believed to be a key mediator of diabetic macular edema (DME). In DME patients, a single intravitreal injection of the corticosteroid triamincolone acetonide (TAA) reduces edematous retinal swelling and improves visual acuity. Taken together, these observations suggest that corticosteroids are inhibitors of VEGF signaling in vivo. The aim of the current study was to evaluate the effects of dexamethasone (DEX) and TAA in a novel rabbit model of VEGF–induced retinal and iris vascular leakage. Methods: Recombinant human VEGF₁₆₅ or vehicle was injected intravitreally in female Dutch Belt rabbits, and scanning ocular fluorophotometry was used one to seven days after injection to non–invasively measure vitreoretinal and anterior chamber fluorescein leakage. VEGF–induced retinal vasculopathy was also assessed with fundus photography, ocular coherence tomography, and fluorescein angiography. During pharmacology studies, rabbits received either vehicle (s.c. or intravitreal), DEX (2 mg/kg daily, s.c.), TAA (2 mg, intravitreal), or indomethacin (20 mg/kg daily, s. c.). Results:Intravitreal VEGF induced a time and dose–dependent increase in retinal and iris vascular leakage. Maximal VEGF–induced leakage was elicited using 500 ng VEGF measured 48 hours after intravitreal injection. VEGF also caused marked retinal vasodilation, vessel tortuousity, fluorescein leakage from superficial retinal vessels, and inner retinal edema. In a 3 day study, the corticosteroid DEX completely blocked VEGF–induced blood–retinal and blood–aqueous barrier breakdown. In the same study, the non–steroidal anti–inflammatory drug, indomethacin, had no affect. In an independent study, using multiple VEGF challenges, 2 mg intravitreal TAA completely blocked VEGF–induced retinal and iris leakage for up to 45 days. Conclusions: A single intravitreal VEGF injection in rabbit caused a time and dose–dependent breakdown of the blood–retinal and blood–aqueous barriers. Intravitreal VEGF–induced vascular leakage was transient and repeatable. The corticosteroids DEX and TAA completely blocked intravitreal VEGF–induced retinal and iris vascular leakage. Our results indicate that corticosteroids are antagonists of downstream VEGF signaling in ocular tissues.

Keywords: growth factors/growth factor receptors • corticosteroids • pharmacology