Abstract WP328: Afilbercept, a Vegf-trap, Reduces Vascular Permeability and Stroke-induced Brain Swelling in Obese Mice

Abstract

Introduction: Brain swelling is a pathological event of ischemic stroke that progresses the enlargement of the brain injury, especially in comorbid conditions. In our previous study, we reported that diabetic obese mice had disproportionately increased stroke-induced brain swelling and that VEGF signaling was involved in this pathophysiology. Aflibercept (VEGF-Trap), an FDA approved drug that targets vascular endothelial growth factor receptor (VEGFR), has been used to treat patients with age-related macular degeneration and metastatic colorectal cancer. This study addressed whether Aflibercept can be used to reduce brain swelling in obesity stroke. Methods: HUVECs were cultured and treated with rVEGF (50 ng/ml) in the presence or absence of VEGF-Trap (1 ug/ml). Permeability was assessed by the incubation with FITC-dextran. Tube formation was also assessed. Diet-induced obese mice were generated by feeding a high-fat diet (HFD) for 8 weeks for males and 12 weeks for females to achieve similar insulin resistance. Their body weight gain and glucose clearance by glucose tolerance test was evaluated. Obese mice were subjected to transient MCAO. VEGF-Trap (10 mg/kg) or IgG (Fc control) was injected intravenously at 3h post-MCAO. VEGFR2 and VEGF-A gene expression was measured by realtime RT-PCR. Infarct size, brainswelling and neurological score were determined. Results: VEGF-Trap reduced rVEGF-A-mediated permeability by 50.0±10.7% (p<0.01, n=7) and tube formation by 28.5±3.5% (p<0.001, n=6) in HUVEC cultures. Stroke-induced VEGFR2 and VEGF-A gene expression was reduced in the mice that received VEGF-trap (38.9±1.0% (VEGFR2) and 34.1±1.4% (VEGF-A), p<0.05, n=7/group). Compared to IgG control, treatment of VEGF-Trap reduced brain swelling (25.3±3.5 % (IgG, n=20) vs 17.3±1.7 % (VEGF-Trap, n=22), p<0.05) and neurological score without reaching a statistical significance (p=0.06). There was no difference in infarct size between the two groups (33.0±3.9 mm 3 (IgG) vs 40.0±4.8 mm 3 (VEGF-Trap), ns). Conclusion: The study demonstrates that targeting VEGF signaling effectively reduces stroke-induced brain swelling in obese mice. The observed benefit suggests the repurposing of VEGF-Trap as a potential therapy in treating stroke in obese subjects.