Abstract
Brain arteriovenous malformations (bAVM) are tangles of abnormal, dilated vessels that directly shunt blood between the arteries and veins. The pathogenesis of bAVM is currently unknown. Patients with hereditary hemorrhagic telangiectasia (HHT) have a higher prevalence of bAVM than the general population. Animal models are important tools for dissecting the disease etiopathogenesis and for testing new therapies. Here, we introduce a method that induces the bAVM phenotype through regional deletion of activin-like kinase 1 (Alk1, the causal gene for HHT2) and vascular endothelial growth factor (VEGF) stimulation.
An erratum to this chapter is available at http://dx.doi.org/10.1007/978-1-4939-0320-7_35
An erratum to this chapter can be found at http://dx.doi.org/10.1007/978-1-4939-0320-7_35
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Kim H, Marchuk DA, Pawlikowska L et al (2008) Genetic considerations relevant to intracranial hemorrhage and brain arteriovenous malformations. Acta Neurochir Suppl 105:199–206
Gabriel RA, Kim H, Sidney S et al (2010) Ten-year detection rate of brain arteriovenous malformations in a large, multiethnic, defined population. Stroke 41:21–26
Kim H, Su H, Weinsheimer S et al (2011) Brain arteriovenous malformation pathogenesis: a response-to-injury paradigm. Acta Neurochir Suppl 111:83–92
Urness LD, Sorensen LK, Li DY (2000) Arteriovenous malformations in mice lacking activin receptor-like kinase-1. Nat Genet 26:328–331
Sorensen LK, Brooke BS, Li DY et al (2003) Loss of distinct arterial and venous boundaries in mice lacking endoglin, a vascular-specific TGFbeta coreceptor. Dev Biol 261:235–250
Park SO, Wankhede M, Lee YJ et al (2009) Real-time imaging of de novo arteriovenous malformation in a mouse model of hereditary hemorrhagic telangiectasia. J Clin Invest 119:3487–3496
Xu B, Wu YQ, Huey M et al (2004) Vascular endothelial growth factor induces abnormal microvasculature in the endoglin heterozygous mouse brain. J Cereb Blood Flow Metab 24:237–244
Hao Q, Su H, Marchuk DA et al (2008) Increased tissue perfusion promotes capillary dysplasia in the ALK1-deficient mouse brain following VEGF stimulation. Am J Physiol Heart Circ Physiol 295:H2250–H2256
Hao Q, Zhu Y, Su H et al (2010) VEGF induces more severe cerebrovascular dysplasia in Endoglin+/- than in Alk1+/- mice. Transl Stroke Res 1:197–201
Walker EJ, Su H, Shen F et al (2011) Arteriovenous malformation in the adult mouse brain resembling the human disease. Ann Neurol 69:954–962
Park SO, Lee YJ, Seki T et al (2008) ALK5- and TGFBR2-independent role of ALK1 in the pathogenesis of hereditary hemorrhagic telangiectasia type 2 (HHT2). Blood 111:633–642
Su H, Lu R, Kan YW (2000) Adeno-associated viral vector-mediated vascular endothelial growth factor gene transfer induces neovascular formation in ischemic heart. Proc Natl Acad Sci U S A 97:13801–13806
Su H, Huang Y, Takagawa J et al (2006) AAV serotype-1 mediates early onset of gene expression in mouse hearts and results in better therapeutic effect. Gene Ther 13:1495–1502
Shen F, Su H, Liu W et al (2006) Recombinant adeno-associated viral vector encoding human VEGF165 induces neomicrovessel formation in the adult mouse brain. Front Biosci 11:3190–3198
Walker EJ, Shen F, Young WL et al (2011) Cerebrovascular casting of adult mouse for 3D imaging and morphological analysis. J Vis Exp (57): e2958
Coyle P, Jokelainen PT (1982) Dorsal cerebral arterial collaterals of the rat. Anat Rec 203:397–404
Maeda K, Hata R, Hossmann KA (1998) Differences in the cerebrovascular anatomy of C57black/6 and SV129 mice. Neuroreport 9:1317–1319
Choi EJ, Walker EJ, Shen F et al (2012) Minimal homozygous endothelial deletion of Eng with VEGF stimulation is sufficient to cause cerebrovascular dysplasia in the adult mouse. Cerebrovasc Dis 33:540–547
Choi EJ, Walker EJ, Degos V et al (2013) Endoglin deficiency in bone marrow is sufficient to cause cerebrovascular dysplasia in the adult mouse after vascular endothelial growth factor stimulation. Stroke 44:795–798
Chen W, Guo Y, Walker EJ et al (2013) Reduced mural cell coverage and impaired vessel integrity after angiogenic stimulation in the Alk1-deficient brain. Arterioscler Thromb Vasc Biol 33:305–310
Shen F, Walker EJ, Jiang L et al (2011) Coexpression of angiopoietin1 with VEGF increases the structural integrity of the blood-brain barrier and reduces atrophy volume. J Cereb Blood Flow Metab 31:2343–2351
Acknowledgements
This work was supported by grants from the NIH National Institute of Neurological Disorders and Stroke—R01 NS027713 (to WLY), P01 NS044155 (to WLY and HS), R21 NS070153 (to HS), and GM008440 (to WC)—and the American Heart Association, AHA 10GRNT3130004 (to HS).
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer Science+Business Media New York
About this protocol
Cite this protocol
Chen, W., Young, W.L., Su, H. (2014). Induction of Brain Arteriovenous Malformation in the Adult Mouse. In: Milner, R. (eds) Cerebral Angiogenesis. Methods in Molecular Biology, vol 1135. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-0320-7_25
Download citation
DOI: https://doi.org/10.1007/978-1-4939-0320-7_25
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4939-0319-1
Online ISBN: 978-1-4939-0320-7
eBook Packages: Springer Protocols