title: Novel brain arteriovenous malformation mouse models for type 1 hereditary hemorrhagic telangiectasia.
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 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), 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.
authors: Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California, United States of America.
authors: Eun-Jung
authors: EJ
authors: Choi
authors: Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California, United States of America.
authors: Wanqiu
authors: W
authors: Chen
authors: Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California, United States of America.
authors: Kristine
authors: K
authors: Jun
authors: Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle, United Kingdom.
authors: Helen M
authors: HM
authors: Arthur
authors: Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California, United States of America ; Department of Neurological Surgery, University of California San Francisco, San Francisco, California, United States of America ; Department of Neurology, University of California San Francisco, San Francisco, California, United States of America.
authors: William L
authors: WL
authors: Young
authors: Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California, United States of America.
authors: Hua
authors: H
authors: Su
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000002:abnormalities / Q000098:blood supply / Q000473:pathology; D004195:Disease Models, Animal; D000071063:Endoglin; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D019426:Integrases / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000378:metabolism; D002538:Intracranial Arteriovenous Malformations / Q000150:complications / Q000188:drug therapy / Q000473:pathology*; D020300:Intracranial Hemorrhages / Q000150:complications / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000473:pathology; D013629:Tamoxifen / Q000494:pharmacology / Q000627:therapeutic use; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000150:complications / Q000188:drug therapy / Q000473:pathology*
chemical_list: D000071063:Endoglin; C502004:Eng protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008840:Microfilament Proteins; D009124:Muscle Proteins; C051615:transgelin; D013629:Tamoxifen; C045073:Cre recombinase; D019426:Integrases