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Olivier Fontaine, Soumaya Hachana, Réjean Couture, Elvire Vaucher, Mark R Lesk; Relationship between VEGF and the Kallikrein-Kinin system in a rat model of laser-induced choroidal neovascularization. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3271. doi: https://doi.org/.
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The neovascular aged-related macular degeneration (AMD) is currently treated by anti-VEGF intravitreal injection in order to stop the neovascularization. In seeking of more efficient treatments to prevent retinal damage, it has been proposed that the kallikrein-kinin system (KKS), a key player in inflammation, could be involved in AMD etiology. However, the role of kinin receptors and their interaction with VEGF in AMD is poorly understood and is addressed herein
Choroidal neovascularization (CNV) was induced in the left eye of male Long-Evans rat. Ten days later, the therapeutic value of kinin B1R blockade was evaluated by eye-drops application of a peptidase resistant kinin B1R antagonist (R-954, 100 ng/5 µL) or by intravitreal injection of kinin B1R siRNA (10 nmol). The contralateral intact eye received vehicle. Alternatively, anti-VEGF (25mg/µL) or IgG control was injected into the vitreal cavity. The impact of those treatments was measured on vascular permeability, leukostasis and on gene expression of retinal inflammatory mediators (qRT-PCR). The distribution of kinin B1R on retinal cell types was investigated by immunocytochemistry
The number of labelled adherent leucocytes was significantly increased in laser-induced CNV compared to control eye. This was significantly reversed by one single injection of anti-VEGF. B1R siRNA and anti-VEGF abolished the increased extravasation of Evans blue dye in laser-induced CNV eyes while R-954 treatment reduced it significantly. The enhanced mRNA expression of inflammatory mediators (B1R, B2R, VEGF-A, VEGF-R2, IL-8, HIF-1a, TNF-a, MCP1, ICAM, VCAM) induced by laser-induced CNV was significantly reduced by anti-VEGF. R-954 inhibited gene expression of kinin receptors, IL-1b and TNF-a but not VEGF-A and VEGF-R2 in CNV-retina. B1R immunolabeling was detected on endothelial, glial and ganglion cells in the CNV-retina. B1R and VEGF-R2 seem to be co-expressed in blood vessels in CNV-retina
This study is the first to highlight the contribution of the KKS in a model of CNV that could be reduced by both anti-VEGF therapy and topically administered B1R antagonist or by B1R siRNA treatment.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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