Abstract
Purpose :
The mechanisms that contribute to VEGF-induced visual dysfunction in diabetic macular edema (DME) are not fully understood. Recently, we have shown that VEGF’s effects on retinal edema are mediated, in part, via the kallikrein/kinin system (KKS). These effects of the KKS on retinal edema are mediated by bradykinin (BK), a potent vasoactive and neuropeptide. This study investigates the effects of intravitreal VEGF and the KKS on electroretinography (ERG) and visual function.
Methods :
Retinal neuronal function was measured using full field dark-adapted ERG at baseline, 2, 24 and 48 hours following intravitreal VEGF (10ng/eye), BK (2µM), plasma kallikrein (Pkal, 50ng/eye), and PBS control. Maximal scotopic responses were obtained using a white light flash (1.4x104 cd/m2) with a duration of 5 ms. Visual acuity in C57BL/6 mice was assessed by OptoMotry system (Cerebral Mechanics, Alberta, Canada) after intravitreal VEGF (200ng/eye), BK or PBS.
Results :
In rat, intravitreal (IVT) injection of VEGF did not affect ERG B-wave amplitude at 24 h (368±28µV) but increased B-wave amplitude at 48 h by 81% (630±66µV, p<0.001) compared to baseline (348±29µV). Systemic administration of the selective Pkal inhibitor VA999272 via a subcutaneously implanted osmotic pump (0.65mg/kg/d) reduced VEGF induced B-wave amplitude by 69% (454±46µV, p=0.002) at 48 h. BK increased B-wave amplitude at 2, 24 and 48 h by 28% (437±30 vs 341±20, p=0.015), 75% (461±46 vs 262±40µV, p<0.001) and 64% (494±32±32 vs 301±53µV, p<0.001), respectively. Intravitreal injection of PKal increased B-wave amplitude at 24 h by 50% (559±42 vs 372±37µV, p<0.01) which was reduced by 59% (448±32µV, p<0.05) with subcutaneous administration of bradykinin receptor antagonism (HOE140 + desArg10Hoe140, 10µg/kg/h). At 36 h post IVT VEGF, visual acuity was reduced by 39% (0.243 vs 0.399 cycles/degree, p=0.002) but not at 12 (0.376) or 24 (0.390) h. For BK, visual acuity was reduced at 6, 12, and 24 h post IVT by 25% (0.264 vs 0.352, p=0.011), 18% (0.294 vs 0.359, p=0.014) and 17% (0.302 vs 0.365, p=0.019), respectively.
Conclusions :
Intravitreal injection of VEGF and components of the KKS cause increased ERG signal amplitudes, which are temporally associated with deficits in visual acuity. These data suggest that the effects of VEGF on visual dysfunction are mediated in part via the KKS and BK’s effects upon the neuroretina.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.