Abstract
Purpose :
Factor XII (FXII) and its activated serine protease form FXIIa have been identified in the vitreous of patients with diabetic macular edema (DME). FXIIa is the primary activator of the kallikrein-kinin system, which has been implicated in DME. The current study investigates the effects of FXII on retinal edema and neuroretinal responses in mice.
Methods :
Age-matched male wild-type (WT) and FXII deficient (FXIIKO) mice received intravitreal injections (1µL) of VEGF (100ng/eye), FXIIa (50ng/eye), or saline control. Retinal thickness was measured at 24 and 48 hours post injection using spectral domain optical coherence tomography. Retinal neuronal function was assessed using full field dark-adapted scotopic electroretinography (ERG) at 48 hours following intravitreal injections. Diabetes was induced in WT and FXIIKO mice by streptozotocin and scotopic ERG was measured after 4 months duration of diabetes and on age-matched non-diabetic controls.
Results :
In WT mice, intravitreal administration of FXIIa or saline (vehicle) increased retinal thickening (RPE to RNFL) by 30.1+2.72 µm vs 4.8+2.4µm (p<0.001) at 24 hrs and 50.7+9.1 vs 15.6+4.6µm (p<0.01) at 48 hrs post injection. Retinal thickening following intravitreal injection of VEGF was reduced by 60% in FXIIKO mice (10.5±2.2µm, n=7) at 48h compared with WT mice (22.4±8.8 µm, n=19, p<0.05). Intravitreal injection of VEGF induced abnormalities in ERG amplitudes for A- and B- waves (244±8, 451±14µV) compared to PBS (167±10, 307±9, p<0.05, n=15) in WT mice. FXIIKO mice were protected from VEGF-induced ERG abnormalities in A- and B- wave amplitude by 73.5% (209±19, 373±31µV, p<0.05, n=8), which were not significantly different than responses in eyes injected with saline vehicle. In WT mice, diabetes decreased ERG amplitudes for A- and B- waves (168±15, 262±21µV, n=9) compared to non-diabetic controls (187±10, 315±13µV, n=15, p<0.01). In FXIIKO mice, A- and B-waves in mice with diabetes (211±10, 347±22µV) were not significantly different from non-diabetic control mice (220±14, 365±19µV, n=10).
Conclusions :
Intravitreal FXIIa induces retinal thickening and FXII deficiency reduces VEGF-stimulated retinal thickening. FXII deficiency is protective against both VEGF- and diabetes-induced changes in ERG responses. These data further indicate that FXIIa may provide a therapeutic target for retinal edema and visual dysfunction in DME.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.