스트렙토조토신 유도 당뇨 생쥐 모델에서 aflibercept의 망막 혈관 주위세포 소실 억제와 비관류 호전 효과 분석

Abstract

Purpose: To examine the efficacy of aflibercept against pericyte loss and perfusion block in relation with leukocyte recruitment in the early stages of streptozotocin-induced diabetic retinopathy (DR) in mice.

Methods: To model DR in mice, streptozotocin (STZ, 150 mg/kg) was intraperitoneally administered to eight-week-old C57BL/6N male mice. At 4 weeks after the STZ injection, the mice were divided into aflibercept-treated (25 mg/kg) and saline-treated groups. Eight weeks after STZ injection, vascular permeability/leakage was measured with fluorescein angiography in living mice. At 4, 6, and 8 weeks after STZ injection, the mouse eyes were enucleated, flat-mounted, and stained for platelet derived growth factor receptor-𝛽 (PDGFR-𝛽) to assess pericyte abundance, for CD45 to assess leukocyte abundance, and with fluorescein isothiocyanate dextran (FITC) to assess perfusion. Vascular endothelial growth factor (VEGF) level was quantified for each group. The effects of aflibercept on pericyte number, perfusion status, and leukocyte recruitment/accumulation were also evaluated.

Results: STZ injection successfully produced a DR model, which showed hyperpermeability of retinal vessels and hypoperfusion of the retina. There were fewer pericytes in the retinas of mice in the aflibercept group relative to the control group. VEGF levels were upregulated in the retinas aflibercept-treated mice. Hypoperfusion of the peripheral retina became evident 6 weeks after STZ injection. Accumulation of aggregated leukocytes increased during the same period and appeared mainly at the border between perfused and non-perfused areas, suggesting a possible cause-effect relationship. VEGF inhibition with aflibercept resulted in decreased leukocyte recruitment, aggregation, perfusion block, and eventual pericyte loss.

Conclusion: Aflibercept attenuated pericyte loss in STZ-induced DR in mice. Consequently, aflibercept was also effective in mitigating the early pathology associated with DR, such as hyperpermeability and hypoperfusion. With these findings, we suggest that anti-VEGF strategies should be considered and further evaluated as possible therapeutic options against the initial changes of DR.