Toggle Main Menu Toggle Search

Open Access padlockePrints

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

Lookup NU author(s): Professor Helen ArthurORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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 Eng-floxed sequence in Eng(2fl/2fl) mice. To create an HHT1 brain AVM mouse model, we used several Cre transgenic mouse lines to delete Eng in different cell-types in Eng(2fl/2fl) mice: R26CreER (all cell types after tamoxifen treatment), SM22a-Cre (smooth muscle and endothelial cell) and LysM-Cre (lysozyme M-positive macrophage). An adenoassociated viral vector expressing vascular endothelial growth factor (AAV-VEGF) was injected into the brain to induce focal angiogenesis. We found that SM22 proportional to-Cre-mediated Eng deletion in the embryo caused AVMs in the postnatal brain, spinal cord, and intestines. Induction of Eng deletion in adult mice using R26CreER plus local VEGF stimulation induced the brain AVM phenotype. In both models, Eng-null endothelial cells were detected in the brain AVM lesions, and formed mosaicism with wildtype endothelial cells. However, LysM-Cre-mediated Eng 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 Eng deletion is insufficient and that endothelial Eng homozygous deletion is required for HHT1 brain AVM development.

Publication metadata

Author(s): Choi EJ, Chen WQ, Jun K, Arthur HM, Young WL, Su H

Publication type: Article

Publication status: Published

Journal: PLOS One

Year: 2014

Volume: 9

Issue: 2

Print publication date: 10/02/2014

Acceptance date: 08/01/2014

Date deposited: 22/05/2014

ISSN (print): 1932-6203

ISSN (electronic):

Publisher: Public Library of Science


DOI: 10.1371/journal.pone.0088511


Altmetrics provided by Altmetric


Funder referenceFunder name
Michael Ryan Zodda Foundation
Leslie Munzer Foundation
P01NS044155National Institutes of Health
R01NS027713National Institutes of Health