Abstract TMP105: Elevation of VEGF Exacerbates Hemorrhage in Mouse Brain Arteriovenous Malformation
Stroke(2019)
Abstract
Background and purpose: High level of VEGF has been implicated in bAVM bleeding and rupture through analyzing the VEGF levels in patients’ blood and in surgically resected bAVM specimens. However, the direct evidence is missing. Using a mouse bAVM model, we tested the hypothesis that elevation of focal VEGF level exacerbates the severity of bAVM hemorrhage. Methods: Brain AVMs were induced in adult mice that have Alk1 (an AVM causal gene) exons 4-6 floxed by injection of an adenoviral vector expressing Cre-recombinase (Ad-Cre) and an adeno-associated viral vector expressing human VEGF (AAV-VEGF) into the basal ganglia. Two doses of AAV-VEGF, 5x10 9 (high) or 2x10 9 (low) viral genomes were used. In addition, the common carotid artery and jugular vein were anastomosis in a group of mice treated with low dose AAV-VEGF 6 weeks after the model induction to induce venous hypertension (VH), because VH increases VEGF level in the brain. Hemorrhages in the bAVM lesions were quantified on brain sections stained with Prussian blue, which detect iron deposition 8 or 9 weeks after model induction. VEGF levels were quantified by ELISA. Results: Compared to mice injected with low dose AAV-VEGF, mice injected with high dose of AAV-VEGF had a higher level of VEGF, larger Prussian blue positive areas in the bAVM lesion at 8 and 9-weeks after model induction (P<0.0001). In the low dose AAV-VEGF group, 69% mice had bAVM hemorrhage, while in the high dose AAV-VEGF group, 100% mice had bAVM hemorrhage. VH increased bAVM hemorrhage in low dose AAV-VEGF group. The overall mortality of bAVM in the high dose AAV-VEGF group was 26.7%, while no mouse died in the low AAV-VEGF group. VH caused a 50% mortality in low dose AAV-VEGF group. Conclusion: Using mouse bAVM models, we demonstrated that the evaluation of VEGF level through viral vector mediated overexpression of VEGF or create VH increases bAVM hemorrhage and mouse mortality.
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