June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Factor XII contributes to VEGF-induced retinal edema and neuroretinal responses in mice
Author Affiliations & Notes
  • Allen Clermont
    KalVista Pharmaceuticals, Cambridge, Massachusetts, United States
  • Nivetha Murugesan
    KalVista Pharmaceuticals, Cambridge, Massachusetts, United States
  • Tuna Ustunkaya
    Beetham Eye Institute, Joslin Diabetes Center, Boston, Massachusetts, United States
  • Lloyd Aiello
    Beetham Eye Institute, Joslin Diabetes Center, Boston, Massachusetts, United States
    Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
  • Edward P Feener
    KalVista Pharmaceuticals, Cambridge, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Allen Clermont Kalvista Pharmaceuticals, Code E (Employment), Kalvista Pharmaceuticals, Code I (Personal Financial Interest); Nivetha Murugesan Kalvista Pharmaceuticals, Code E (Employment), Kalvista Pharmaceuticals, Code I (Personal Financial Interest); Tuna Ustunkaya None; Lloyd Aiello Kalvista Pharmaceuticals, Code I (Personal Financial Interest), Kalvista Pharmaceuticals, Code O (Owner); Edward Feener Kalvista Pharmaceuticals, Code I (Personal Financial Interest), Kalvista Pharmaceuticals, Code O (Owner)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 5411. doi:
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      Allen Clermont, Nivetha Murugesan, Tuna Ustunkaya, Lloyd Aiello, Edward P Feener; Factor XII contributes to VEGF-induced retinal edema and neuroretinal responses in mice. Invest. Ophthalmol. Vis. Sci. 2023;64(8):5411.

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      © ARVO (1962-2015); The Authors (2016-present)

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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.

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