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

Eun-Jung Choi,Kristine Jun,Hua Su,Helen M Arthur,William L Young,Wanqiu Chen,Klaus Brusgaard

doi:10.1371/journal.pone.0088511

Eun-Jung Choi, Kristine Jun + Show 5 more

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https://doi.org/10.1371/journal.pone.0088511

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Abstract

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 Eng2fl/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 Eng2fl/2fl mice: R26CreER (all cell types after tamoxifen treatment), SM22α-Cre (smooth muscle and endothelial cell) and LysM-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 SM22α-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.

Highlights

Hereditary hemorrhagic telangiectasia (HHT), known as Osler-Weber-Rendu (OWR) syndrome, is the first identified human disease caused by defects in a transforming growth factor-ß (TGF-ß) superfamily receptor [1]
Most of HHT cases are categorized into either HHT type 1 (HHT1) caused by mutations in endoglin (ENG), a TGF-ß type III auxiliary receptor mapped on chromosome 9 [1], or HHT type 2 (HHT2) caused by mutations in activin receptor-like kinase 1 (ACVRL1; ALK1), a TGF-ß type I serine-threonine kinase receptor located in chromosome 12 [3]
To test if SM22aCre-mediated Eng deletion in the embryo leads to postnatal brain arteriovenous malformation (AVM), we crossbred Eng2fl/2fl mice with SM22a-Cre mice

Summary

Introduction

Hereditary hemorrhagic telangiectasia (HHT), known as Osler-Weber-Rendu (OWR) syndrome, is the first identified human disease caused by defects in a transforming growth factor-ß (TGF-ß) superfamily receptor [1]. It is an autosomal dominant genetic disorder of the blood vessels that manifests epistaxis, mucocutaneous telangiectases, and arteriovenous malformations (AVMs) in multiple organs including the brain, lung, liver, gastrointestinal tract, and spinal cord [2]. Brain AVM is a tangle of abnormal vessels called nidus, where blood directly shunts from arteries into veins without passing the capillary bed. No specific medical therapy is available for brain AVM patients

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