Novel Brain Arteriovenous Malformation Mouse Models for Type 1 Hereditary Hemorrhagic Telangiectasia

<div><p>Endoglin (ENG) is a causative gene of type 1 hereditary hemorrhagic telangiectasia (HHT1). HHT1 patients have a higher prevalence of brain arteriovenous malformation (AVM) than the general population and patients with other HHT subtypes. The pathogenesis of brain AVM in HHT1 patients is currently unknown and no specific medical therapy is available to treat patients. Proper animal models are crucial for identifying the underlying mechanisms for brain AVM development and for testing new therapies. However, creating HHT1 brain AVM models has been quite challenging because of difficulties related to deleting <i>Eng</i>-floxed sequence in <i>Eng^2fl/2fl</i> mice. To create an HHT1 brain AVM mouse model, we used several Cre transgenic mouse lines to delete <i>Eng</i> in different cell-types in <i>Eng^2fl/2fl</i> mice: <i>R26</i>CreER (all cell types after tamoxifen treatment), <i>SM22α</i>-Cre (smooth muscle and endothelial cell) and <i>LysM</i>-Cre (lysozyme M-positive macrophage). An adeno-associated viral vector expressing vascular endothelial growth factor (AAV-VEGF) was injected into the brain to induce focal angiogenesis. We found that <i>SM22α</i>-Cre-mediated <i>Eng</i> deletion in the embryo caused AVMs in the postnatal brain, spinal cord, and intestines. Induction of <i>Eng</i> deletion in adult mice using <i>R26</i>CreER plus local VEGF stimulation induced the brain AVM phenotype. In both models, <i>Eng</i>-null endothelial cells were detected in the brain AVM lesions, and formed mosaicism with wildtype endothelial cells. However, <i>LysM</i>-Cre-mediated <i>Eng</i> deletion in the embryo did not cause AVM in the postnatal brain even after VEGF stimulation. In this study, we report two novel HHT1 brain AVM models that mimic many phenotypes of human brain AVM and can thus be used for studying brain AVM pathogenesis and testing new therapies. Further, our data indicate that macrophage <i>Eng</i> deletion is insufficient and that endothelial <i>Eng</i> homozygous deletion is required for HHT1 brain AVM development.</p>