Postdoctoral Research Fellow Barrow Neurological Institute Phoenix, Arizona, United States
Disclosure(s):
Lea Scherschinski, MD: No financial relationships to disclose
Introduction: Existing mouse models of brain AVMs are restricted by a lack of specificity to the brain that results in hemorrhagic AVMs in internal organs and is associated with poor long-term survival. The goal of this project was to develop a novel experimental mouse model using targeted drug delivery to induce localized brain AVMs in transgenic mice.
Methods: ROSA26CreER;Alk1f/f mice with ubiquitous CreER expression were used. 4-hydroxytamoxifen (4-OHTM) was stereotactically delivered into the right striatum, left parietal cortex, or cerebellum of neonatal mice at postnatal day 1. Brain AVMs were evaluated with systemic latex dye perfusion, 3D time-of-flight magnetic resonance angiography, immunofluorescence, and Prussian Blue Staining.
Results: Alk1-inducible knockout (Alk1-iKO) mice injected stereotactically with 4-OHTM developed brain AVMs with 68% (21/31) frequency in the right striatum, 72% (13/18) in the left parietal cortex, and 44% (4/9) in the cerebellum. Brain AVMs formed in or near the injection site with 95% accuracy (36/38). A subset of mice (8%, [3/38]) presented with a communicating hydrocephalus due to CSF malabsorption. AVM development was restricted to the brain, without AVMs developing in internal organs (n=38). R26CreER;Alk1/mTmG reporter mice were used to visualize the local genetic recombination at the injection site. The 4-week mortality was 5% (2/38), and longitudinally monitored mice demonstrated good survival at 7 months of age (86%, [6/7]). The brain AVMs closely approximate the phenotypical hallmarks present in human brain AVMs, including microhemorrhaging and inflammation.
Conclusion : We present the first experimental mouse model with local, CreER-mediated induction of brain AVMs. The model generates brain AVMs with high efficiency in different target regions that closely resemble the human brain AVM phenotype. Altogether, this model serves as a novel discovery platform to accelerate the ongoing investigations of brain AVM pathogenesis, rupture, and preclinical testing of novel therapeutics.
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