Cellular Analysis of BAVM Regression in a Mouse Model
Initial Award Abstract
Smoking has been shown to greatly increase the chances of hemorrhagic stroke. Vascular abnormalities, primarily Brain Arteriovenous Malformations (BAVMs), are responsible for half of all hemorrhagic stroke in young people. Approximately 600,000 people worldwide harbor BAVMs that can potentially rupture, leading to stroke and death. The disease is poorly understood, and while surgical treatment can be effective, many BAVMs are inaccessible.
We recently reported a transgenic mouse model of BAVM-like abnormalities induced by endothelial specific and temporally regulated expression of constitutively-active Notch4 (Notch4*). As in the human disease, arteries and veins were connected through enlarged vessels that bypass the capillary bed. We found that, as in humans, these enlarged arteriovenous connections resulted in the shunting of blood directly from arteries to veins, were prone to hemorrhagic rupture, and resulted in stroke. It is commonly thought that BAVMs do not regress, but rather that they continue to enlarge and eventually rupture. Temporal regulation of Notch4* expression in these mice allows us to test the hypothesis that BAVMs will regress following suppression of the causal stimulus.
The specific aims of this proposal are to determine whether the hallmarks of BAVM, enlarged arteriovenous connections and high-flow arteriovenous shunting, can be reversed by repression of Notch4*. If true, these findings would suggest that if the stimulus for human BAVM can be blocked, the regression of the vascular abnormalities may occur through latent endogenous pathways. In vivo imaging of the specific endothelial cell (EC) mechanisms underlying this regression will reveal normal endothelial processes that may be promoted to reverse the disease. |