Plasma Kallikrein Mediates Vascular Endothelial Growth Factor-Induced Retinal Dysfunction and Thickening
| Autor: | Qunfang Zhou, Allen C. Clermont, Peter A. Robson, Nivetha Murugesan, D. Michael Evans, Louise J. Rushbrooke, Edward P. Feener, Takeshi Kita, Lloyd Paul Aiello |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Vascular Endothelial Growth Factor A retinal edema SD-OCT medicine.medical_specialty plasma kallikrein Blotting Western Vascular permeability Macular Edema Retina Capillary Permeability Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound Mice Internal medicine Medicine Animals Evans Blue business.industry Retinal Kallikrein VEGF Extravasation Rats Vascular endothelial growth factor Mice Inbred C57BL Vascular endothelial growth factor A 030104 developmental biology medicine.anatomical_structure Endocrinology chemistry Intravitreal Injections business Tomography Optical Coherence circulatory and respiratory physiology |
| Zdroj: | Investigative Ophthalmology & Visual Science |
| ISSN: | 1552-5783 |
| Popis: | PURPOSE Plasma kallikrein is a serine protease and circulating component of inflammation, which exerts clinically significant effects on vasogenic edema. This study examines the role of plasma kallikrein in VEGF-induced retinal edema. METHODS Intravitreal injections of VEGF and saline vehicle were performed in plasma prekallikrein-deficient (KLKB1-/-) and wild-type (WT) mice, and in both rats and mice receiving a selective plasma kallikrein inhibitor, VA999272. Retinal vascular permeability (RVP) and retinal thickness were measured by Evans blue permeation and optical coherence tomography, respectively. The retinal kallikrein kinin system was examined by Western blotting and immunohistochemistry. Retinal neovascularization was investigated in KLKB1-/- and WT mice subjected to oxygen-induced retinopathy. RESULTS Vascular endothelial growth factor-induced RVP and retinal thickening were reduced in KLKB1-/- mice by 68% and 47%, respectively, compared to VEGF responses in WT mice. Plasma kallikrein also contributes to TNFα-induced retinal thickening, which was reduced by 52% in KLKB1-/- mice. Systemic administration of VA999272 reduced VEGF-induced retinal thickening by 57% (P < 0.001) in mice and 53% (P < 0.001) in rats, compared to vehicle-treated controls. Intravitreal injection of VEGF in WT mice increased plasma prekallikrein in the retina, which was diffusely distributed throughout the inner and outer retinal layers. Avascular and neovascular areas induced by oxygen-induced retinopathy were similar in WT and KLKB1-/- mice. CONCLUSIONS Vascular endothelial growth factor increases extravasation of plasma kallikrein into the retina, and plasma kallikrein is required for the full effects of VEGF on RVP and retinal thickening in rodents. Systemic plasma kallikrein inhibition may provide a therapeutic opportunity to treat VEGF-induced retina edema. |
| Databáze: | OpenAIRE |
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