July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
Complement C3 mediates vascular endothelial growth factor (VEGF) induced retinal edema but not visual dysfunction in mice.
Author Affiliations & Notes
  • Allen C Clermont
    Beetham Eye Institute, Joslin Diabetes Center, Stoughton, Massachusetts, United States
  • Alex Feener
    Beetham Eye Institute, Joslin Diabetes Center, Stoughton, Massachusetts, United States
  • Nivetha Murugesan
    Kalvista Pharmaceuticals, Inc, Cambridge, Massachusetts, United States
  • Lloyd P Aiello
    Beetham Eye Institute, Joslin Diabetes Center, Stoughton, Massachusetts, United States
    Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
  • Edward Feener
    Kalvista Pharmaceuticals, Inc, Cambridge, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Allen Clermont, Kalvista Pharmaceuticals, Inc (C); Alex Feener, None; Nivetha Murugesan, Kalvista Pharmaceuticals, Inc (E); Lloyd Aiello, Kalvista Pharmaceuticals, Inc (I), Kalvista Pharmaceuticals, Inc (C), Mingsight (C), Novo Nordisk (C), Optos (R), Retinal Solutions (C); Edward Feener, Kalvista Pharmaceuticals, Inc (E)
  • Footnotes
    Support  Massachusetts Lions Eye Research Fund
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 2791. doi:
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      Allen C Clermont, Alex Feener, Nivetha Murugesan, Lloyd P Aiello, Edward Feener; Complement C3 mediates vascular endothelial growth factor (VEGF) induced retinal edema but not visual dysfunction in mice.. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2791.

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

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Abstract

Purpose : The mechanisms contributing to VEGF-induced visual dysfunction in diabetic macular edema (DME) are not fully understood. We have previously shown that plasma kallikrein contributes to VEGF’s effects on both retinal thickening and abnormal scotopic ERG responses. Moreover, we have shown that C3 deficiency in mice reduced both VEGF- and bradykinin-induced retinal thickening, suggesting that C3 is a downstream mediator of retinal edema. However, the role of C3 in visual function is not yet available. The current study investigates the role of C3 in VEGF induced visual dysfunction in mice and examines the correlation of retinal edema with visual deficit.

Methods : Age-matched male wildtype (WT) and C3 deficient (C3-/-) mice received IVT injections (1µL) of VEGF (100ng/eye) or saline control. Retinal thickness was measured using spectral domain optical coherence tomography. Retinal neuronal function was assessed using maximal scotopic full field dark-adapted ERG at 48 hours post IVT. Optokinetic (Okn) responses were measured at baseline, 1, 2, and 3 days post IVT injections.

Results : At 48 hours after IVT injection in WT mice, VEGF increased total retinal thickness (RPE to RNFL) from baseline vs PBS (30.8±2.3µm vs 3.6±1.1µM, n=9, p<0.001), increased ERG A- and B-wave amplitude (137±10 to 208±15 µV and 243±14 to 371±15 µV, N=10, p<0.05, respectively) and decreased Okn spatial frequency response by 22.4% (0.323±0.014 vs 0.416±0.017 cycles/degree, n=10, p<0.001). VEGF induced change in total retinal thickness was reduced by 71.1% (to 11.5±1.6µm, n=12) in C3-/- mice (p<0.001) compared to WT mice and was increased compared to contralateral eyes injected with PBS (3.6±1.2µm, p<0.01). VEGF increased ERG amplitudes for A- and B- waves (184±12, 341±21µV) compared to PBS (147±13, 248±18, p<0.05) in C3-/- mice, which were similar to VEGF-stimulated amplitudes in WT mice. Okn spatial frequency response was reduced by 18.3% (0.329±0.018 vs 0.405±0.016 cycles/degree, p<0.05) by VEGF compared to PBS in C3-/- mice with no significant difference compared to responses in WT mice.

Conclusions : This study demonstrates that C3 deficiency reduces VEGF-stimulated retinal thickening but does not ameliorate VEGF’s effects on ERG or Okn responses. These data suggest that C3 may contribute to divergent effects of VEGF on retinal edema and visual dysfunction.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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