Plasma Kallikrein Mediates Vascular Endothelial Growth Factor–Induced Retinal Dysfunction and Thickening

Abstract

PurposePlasma 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.MethodsIntravitreal 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.ResultsVascular 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.ConclusionsVascular 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.

The effects of anti‐VEGF and kinin B1 receptor blockade on retinal inflammation in laser‐induced choroidal neovascularization

“…The cellular distribution of B 1 receptors also overlapped VEGF‐R2 in the retina in the CNV model. Whereas B 1 receptors and VEGF may interact in the retina (Clermont et al, ; Kita et al, ), only three studies have explored the role of the KKS in AMD aetiology. The first showed that the KKS was a positive regulator of CNV through the additive effects of a B 2 receptor antagonist and ACE inhibition on the reduction of CNV (Nagai et al, ).…”

“…The co‐localization of VEGF‐R2 and B 1 receptors on retinal blood vessels is congruent with the possibility that VEGF acts partly through the KKS system. Both VEGF and B 1 receptors caused breakdown of the blood‐retinal barrier in numerous ocular diseases, including neovascular AMD (Clermont et al, ; Gragoudas et al, ; Qaum et al, ; Saishin et al, ). A single anti‐VEGF IVT injection reduced the formation of vascular damage in retina and prevented the increase in retinal vascular permeability in laser‐induced CNV, concomitant with a down‐regulation of B 1 and B 2 receptors.…”

“…A single anti‐VEGF IVT injection reduced the formation of vascular damage in retina and prevented the increase in retinal vascular permeability in laser‐induced CNV, concomitant with a down‐regulation of B 1 and B 2 receptors. Accordingly, a recent study has shown that the full effect of VEGF on retinal vascular hyperpermeability is dependent on plasma kallikrein (Clermont et al, ).…”

“…The overexpression of TNF‐α, VEGF, and IL‐1β along with increased density of macrophages has been shown in excised choroidal neovascular membranes of AMD patients, as well as in laser‐induced CNV (Grossniklaus et al, ; Sheridan et al, ; Xie et al, ; Zou, Xu, & Chiou, ). These molecules may promote angiogenesis (Lavalette et al, ; Yang, Wang, Qian, Zhang, & Huang, ) and vascular hyperpermeability (Clermont et al, ). Leukocyte adhesion and the breakdown of the blood‐retinal barrier involve adhesion molecules such as vascular cell adhesion molecule‐1 (VCAM‐1), E‐selectin, and intercellular adhesion molecule‐1 (ICAM‐1), which are overexpressed in the presence of VEGF in endothelial cells (Kim et al, ).…”

Curcumin Delays Retinal Degeneration by Regulating Microglia Activation in the Retina of rd1 Mice

“…In addition, intravitreal injection can be used to distinguish between the treated and untreated eye of a mouse [62-66]. Furthermore, using curcumin in utero might inhibit degeneration entirely [28], given that it might be a better way to use curcumin prenatally for those who at high risk for RP.…”