Intraocular Hemorrhage Causes Retinal Vascular Dysfunction via Plasma Kallikrein

Abstract

PURPOSE. Retinal hemorrhages occur in a variety of sightthreatening conditions including ocular trauma, high altitude retinopathy, and chronic diseases such as diabetic and hypertensive retinopathies. The goal of this study is to investigate the effects of blood in the vitreous on retinal vascular function in rats.METHODS. Intravitreal injections of autologous blood, plasma kallikrein (PK), bradykinin, and collagenase were performed in Sprague-Dawley and Long-Evans rats. Retinal vascular permeability was measured using vitreous fluorophotometry and Evans blue dye permeation. Leukostasis was measured by fluorescein isothiocyanate-coupled concanavalin A lectin and acridine orange labeling. Retinal hemorrhage was examined on retinal flatmounts. Primary cultures of bovine retinal pericytes were cultured in the presence of 25 nM PK for 24 hours. The pericyte-conditioned medium was collected and the collagen proteome was analyzed by tandem mass spectrometry.RESULTS. Intravitreal injection of autologous blood induced retinal vascular permeability and retinal leukostasis, and these responses were ameliorated by PK inhibition. Intravitreal injections of exogenous PK induced retinal vascular permeability, leukostasis, and retinal hemorrhage. Proteomic analyses showed that PK increased collagen degradation in pericyteconditioned medium and purified type IV collagen. Intravitreal injection of collagenase mimicked PK's effect on retinal hemorrhage.CONCLUSIONS. Intraocular hemorrhage increases retinal vascular permeability and leukostasis, and these responses are mediated, in part, via PK. Intravitreal injections of either PK or collagenase, but not bradykinin, induce retinal hemorrhage in rats. PK exerts collagenase-like activity that may contribute to blood-retinal barrier dysfunction. (Invest Ophthalmol Vis Sci.

Plasma kallikrein mediates brain hemorrhage and edema caused by tissue plasminogen activator therapy in mice after stroke

“…49,50 We have previously shown that PKal induces proteolysis of basement membrane and extracellular matrix proteins including multiple collagen isoforms, laminin b1 and g1, nidogen 1 and 2, and fibronectin in brain astrocyte and pericytes. 26,51 Moreover, PKal can interfere with collageninduced platelet activation leading to intracerebral hematoma expansion in rodent models. 11 These reports have revealed that PKal has collagen-binding and collagenase-like activities that might facilitate hemorrhage under certain pathological conditions.…”

“…tPA induced concentration-dependent increases in kallikrein-like activity (P , .01 vs vehicle; Figure 1A). The contribution of PKal to tPAstimulated kallikrein activity was demonstrated using a selective PKal inhibitor BPCCB 25,26 ( Figure 1A, insert) and PPK-deficient plasma ( Figure 1B), which decreased substrate hydrolysis by 83% and 74%, respectively. To investigate the factors that may contribute to tPA-mediated PKal activity, we incubated tPA (360 nM) with normal human plasma and with plasma-depleted in plasminogen or FXII.…”

“…A selective PKal inhibitor BPCCB (1-benzyl-1H-pyrazole-4-carboxylic acid 4-carbamimidoyl-benzylamide) 25,26 in 10% PEG400 in saline at doses of 1, 3, and 10 mg/kg was administered in a total volume of 100 mL, as a 50 mL bolus and 50 mL infused at 2 mL/min over 15 minutes before tPA infusion. Recombinant tPA (10 mg/kg) was administered at a dose typically used in rodents, 8,[27][28][29] which is higher than the clinical dose of 0.9 mg/kg in humans.…”

The kallikrein system in retinal damage/protection

“…It has been reported that intraocular hemorrhage causes retinal vascular dysfunction via the action of plasma kallikrein (Liu et al, 2013). These data indicate that the effects of plasma-or tissue-derived kallikrein are different.…”

“…Moreover, the contribution of the kininkallikrein system to developing CNV was limited (Nagai et al, 2007). However, the plasma kallikrein correlates with intraocular hemorrhage and prokallikrein increases the retinal thickness (Clermont et al, 2011;Liu et al, 2013). These reports suggest that plasma kallikrein and prokallikrein may cause partial aggravation of AMD.…”