Abstract 187: Constitutively Active Notch4 Elicits Brain Arteriovenous Malformations through Capillary Enlargement
Brain arteriovenous (AV) malformation (BAVM) is characterized by focal lesions of enlarged, tangled vessels that shunt blood from arteries to veins. BAVMs can rupture and cause life-threatening stroke. The origin of BAVM is currently unknown. We have developed a transgenic mouse model of BAVM via endothelial expression of constitutively-active Notch4 (Notch4*). Here, using two-photon excited fluorescence microscopy through chronically-implanted cranial windows, we obtained 4D data on the formation of BAVMs in live animals. We found that BAVMs arose from enlargement of pre-existing capillaries - judged as vessels with capillary diameter and blood flow as well as the absence of smooth muscle coverage. Capillary enlargement began promptly following the start of Notch4* expression and often occurred before increases in blood flow. Supporting the capillary origin of BAVMs, alterations in Notch signaling in endothelial cells of capillaries and veins, but not arteries, affected BAVM formation. Although the initiation of capillary enlargement was widespread, more proximal, lower resistance, AV connections grew into AVMs at the expense of more distal AV connections, by increasing in diameter and blood flow velocity through a positive feedback effect. Our data uncovers a mechanism underlying the focal BAVM formation elicited by a perturbation in gene expression throughout the endothelium.
- © 2012 by American Heart Association, Inc.