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Allen C Clermont, Nivetha Murugesan, Tuna Ustunkaya, Brianna Mastromarino, Lloyd P Aiello, Edward P Feener; Effects of Vascular endothelial growth factor (VEGF) on electroretinogram (ERG) amplitude in rats are mediated by bradykinin.. Invest. Ophthalmol. Vis. Sci. 2017;58(8):5347.
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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 in rodents are partly mediated via plasma kallikrein (PKal) and bradykinin (BK). This study investigates the effects of intravitreal VEGF and the kallikrein kinin system (KKS) on electroretinographic (ERG) responses in rats.
Ocular PKal activity was measured by IVIS Spectrum CT using fluorogenic PKal substrate. Rat retinal neuronal function was measured using full field dark-adapted ERG at baseline, 2, 24 and 48 hours following intravitreal (IVT) injections (5µL) of VEGF (10ng/eye), BK (2µM), Pkal (50ng/eye), and saline control. Maximal scotopic responses were obtained using a 5ms white light flash (1.4x104 cd/m2).
At 24 hrs after IVT, VEGF increased fluorescence of PKal substrate in the vitreous compared to saline injected eyes (12.7±1.5 vs 4.9±1.3 avg radiance p<0.05). IVT injection of VEGF did not affect ERG at 24 hrs but increased A and B-wave amplitudes at 48 hrs by 75% (251±10 v 144±12µV, p<0.01) and 73% (619±26 v 357±29µV, p<0.01), respectively, compared to baseline. The B to A-wave amplitude ratio was not different between PBS and VEGF at 48 hrs (2.53 vs 2.46). Administration of selective Pkal inhibitor VA999272 via subcutaneous osmotic pump (0.65mg/kg/d) reduced VEGF induced B-wave amplitude by 69% (454±46µV, p=0.002) at 48 hrs. BK IVT increased B-wave amplitude at 2, 24 and 48 hrs by 28% (437±30 vs 341±20µV, p=0.015), 75% (461±46 vs 262±40µV, p<0.001) and 64% (494±32±32 vs 301±53µV, p<0.001). PKal IVT increased B-wave amplitude at 24 hrs by 50% (559±42 vs 372±37µV, p<0.01), which was reduced by 59% (448±32µV, p<0.05) with subcutaneous administration of B2 and B1 receptor antagonists HOE140 + desArg10Hoe140 (10µg/kg/h). Oral treatment with nitric oxide inhibitor L-Name (0.1mg/mL) reduced VEGF induced B-wave amplitude at 48 hrs by 75% (from 455±20 to 325±25µV, p<0.05) compared to PBS (281±19µV).
Intravitreal injection of VEGF causes activation of the KKS leading to increased ERG signal amplitudes. KKS activation acts upon the neuroretina through BK, which is blocked by BK receptor antagonism and nitric oxide inhibition. These data suggest that the effects of VEGF on visual dysfunction are mediated, in part, via the KKS and nitric oxide.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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