Increased tissue perfusion promotes capillary dysplasia in the ALK1-deficient mouse brain following VEGF stimulation

Abstract

Loss-of-function activin receptor-like kinase 1 gene mutation (ALK1+/−) is associated with brain arteriovenous malformations (AVM) in hereditary hemorrhagic telangiectasia type 2. Other determinants of the lesional phenotype are unknown. In the present study, we investigated the influence of high vascular flow rates on ALK1+/− mice by manipulating cerebral blood flow (CBF) using vasodilators. Adult male ALK1+/− mice underwent adeno-associated viral-mediated vascular endothelial growth factor (AAVVEGF) or lacZ (AAVlacZ as a control) gene transfer into the brain. Two weeks after vector injection, hydralazine or nicardipine was infused intraventricularly for another 14 days. CBF was measured to evaluate relative tissue perfusion. We analyzed the number and morphology of capillaries. Results demonstrated that hydralazine or nicardipine infusion increased focal brain perfusion in all mice. It was noted that focal CBF increased most in AAVVEGF-injected ALK1+/− mice following hydralazine or nicardipine infusion (145 ± 23% or 150 ± 11%; P < 0.05). There were more detectable dilated and dysplastic capillaries (2.4 ± 0.3 or 2.0 ± 0.4 dysplasia index; P < 0.01) in the brains of ALK1+/− mice treated with AAVVEGF and hydralazine or nicardipine compared with the mice treated with them individually. We concluded that increased focal tissue perfusion and angiogenic factor VEGF stimulation could have a synergistic effect to promote capillary dysplasia in a genetic deficit animal model, which may have relevance to further studies of AVMs.