{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T22:51:34Z","timestamp":1792623094661,"version":"4.5.0"},"reference-count":47,"publisher":"Journal of Neurosurgery Publishing Group (JNSPG)","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,7,1]]},"abstract":"<jats:sec>\n<jats:title>OBJECTIVE<\/jats:title>\n<jats:p>Hereditary hemorrhagic telangiectasia is the only condition associated with multiple inherited brain arteriovenous malformations (AVMs). Therefore, a mouse model was developed with a genetics-based approach that conditionally deleted the causative activin receptor-like kinase 1 (<jats:italic>Acvrl1<\/jats:italic> or <jats:italic>Alk1<\/jats:italic>) gene. Radiographic and histopathological findings were correlated, and AVM stability and hemorrhagic behavior over time were examined.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>METHODS<\/jats:title>\n<jats:p><jats:italic>Alk1<\/jats:italic>-floxed mice were crossed with deleter mice to generate offspring in which both copies of the <jats:italic>Alk1<\/jats:italic> gene were deleted by <jats:italic>Tagln<\/jats:italic>-Cre to form brain AVMs in the mice. AVMs were characterized using MRI, MRA, and DSA. Brain AVMs were characterized histopathologically with latex dye perfusion, immunofluorescence, and Prussian blue staining.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>RESULTS<\/jats:title>\n<jats:p>Brains of 55 <jats:italic>Tagln<\/jats:italic>-Cre<jats:sup>+<\/jats:sup>;<jats:italic>Alk1<\/jats:italic><jats:sup>2f\/2f<\/jats:sup> mutant mice were categorized into three groups: no detectable vascular lesions (group 1; 23 of 55, 42%), arteriovenous fistulas (AVFs) with no nidus (group 2; 10 of 55, 18%), and nidal AVMs (group 3; 22 of 55, 40%). Microhemorrhage was observed on MRI or MRA in 11 AVMs (50%). AVMs had the angiographic hallmarks of early nidus opacification, a tangle of arteries and dilated draining veins, and rapid shunting of blood flow. Latex dye perfusion confirmed arteriovenous shunting in all AVMs and AVFs. Microhemorrhages were detected adjacent to AVFs and AVMs, visualized by iron deposition, Prussian blue staining, and macrophage infiltration using CD68 immunostaining. Brain AVMs were stable on serial MRI and MRA in group 3 mice (mean age at initial imaging 2.9 months; mean age at last imaging 9.5 months).<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>CONCLUSIONS<\/jats:title>\n<jats:p>Approximately 40% of transgenic mice satisfied the requirements of a stable experimental AVM model by replicating nidal anatomy, arteriovenous hemodynamics, and microhemorrhagic behavior. Transgenic mice with AVFs had a recognizable phenotype of hereditary hemorrhagic telangiectasia but were less suitable for experimental modeling. AVM pathogenesis can be understood as the combination of conditional <jats:italic>Alk1<\/jats:italic> gene deletion during embryogenesis and angiogenesis that is hyperactive in developing and newborn mice, which translates to a congenital origin in most patients but an acquired condition in patients with a confluence of genetic and angiogenic events later in life. This study offers a novel experimental brain AVM model for future studies of AVM pathophysiology, growth, rupture, and therapeutic regression.<\/jats:p>\n<\/jats:sec>","DOI":"10.3171\/2021.6.jns21717","type":"journal-article","created":{"date-parts":[[2021,11,5]],"date-time":"2021-11-05T20:33:56Z","timestamp":1636144436000},"page":"163-174","source":"Crossref","is-referenced-by-count":15,"title":["Novel experimental model of brain arteriovenous malformations using conditional Alk1 gene deletion in transgenic mice"],"prefix":"10.3171","volume":"137","author":[{"given":"Chul","family":"Han","sequence":"first","affiliation":[{"name":"Barrow Aneurysm and AVM Research Center, Department of Translational Neuroscience, Barrow Neurological Institute, St. Joseph\u2019s Hospital and Medical Center, Phoenix;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Lang","sequence":"additional","affiliation":[{"name":"Departments of Neurosurgery and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Candice L.","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Barrow Aneurysm and AVM Research Center, Department of Translational Neuroscience, Barrow Neurological Institute, St. Joseph\u2019s Hospital and Medical Center, Phoenix;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernesto","family":"Luna Melendez","sequence":"additional","affiliation":[{"name":"Ivy Brain Tumor Center, Department of Translational Neuroscience, Barrow Neurological Institute, St. Joseph\u2019s Hospital and Medical Center, Phoenix, Arizona"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shwetal","family":"Mehta","sequence":"additional","affiliation":[{"name":"Ivy Brain Tumor Center, Department of Translational Neuroscience, Barrow Neurological Institute, St. Joseph\u2019s Hospital and Medical Center, Phoenix, Arizona"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory H.","family":"Turner","sequence":"additional","affiliation":[{"name":"Neuroimaging, Barrow Neurological Institute, St. Joseph\u2019s Hospital and Medical Center, Phoenix; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael T.","family":"Lawton","sequence":"additional","affiliation":[{"name":"Barrow Aneurysm and AVM Research Center, Department of Translational Neuroscience, Barrow Neurological Institute, St. Joseph\u2019s Hospital and Medical Center, Phoenix;"},{"name":"Departments of Neurosurgery and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. Paul","family":"Oh","sequence":"additional","affiliation":[{"name":"Barrow Aneurysm and AVM Research Center, Department of Translational Neuroscience, Barrow Neurological Institute, St. Joseph\u2019s Hospital and Medical Center, Phoenix;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1754","reference":[{"issue":"1","key":"b1","series-title":"J Clin Neurosci","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1016\/j.jocn.2009.02.044","article-title":"Comparison of an animal model of arteriovenous malformation with human arteriovenous malformation","volume":"17","author":"Tu J","year":"2010","unstructured":"Tu J, Karunanayaka A, Windsor A, Stoodley MA. Comparison of an animal model of arteriovenous malformation with human arteriovenous malformation. J Clin Neurosci. 2010;17(1):96\u2013102.1991019710.1016\/j.jocn.2009.02.044"},{"issue":"2","key":"b2","series-title":"J Neurosurg","doi-asserted-by":"publisher","first-page":"267","DOI":"10.3171\/jns.1997.87.2.0267","article-title":"Redefined role of angiogenesis in the pathogenesis of dural arteriovenous malformations","volume":"87","author":"Lawton MT","year":"1997","unstructured":"Lawton MT, Jacobowitz R, Spetzler RF. Redefined role of angiogenesis in the pathogenesis of dural arteriovenous malformations. J Neurosurg. 1997;87(2):267\u2013274.925409210.3171\/jns.1997.87.2.0267"},{"issue":"1","key":"b3","series-title":"J Neurosurg","doi-asserted-by":"publisher","first-page":"136","DOI":"10.3171\/jns.2005.103.1.0136","article-title":"Angiogenesis in the brain during development: the effects of vascular endothelial growth factor and angiopoietin-2 in an animal model","volume":"103","author":"Vates GE","year":"2005","unstructured":"Vates GE, Hashimoto T, Young WL, Lawton MT. Angiogenesis in the brain during development: the effects of vascular endothelial growth factor and angiopoietin-2 in an animal model. J Neurosurg. 2005;103(1):136\u2013145.10.3171\/jns.2005.103.1.0136"},{"issue":"4","key":"b4","series-title":"Nat Genet","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1038\/ng1294-345","article-title":"Endoglin, a TGF-\u03b2 binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1","volume":"8","author":"McAllister KA","year":"1994","unstructured":"McAllister KA, Grogg KM, Johnson DW, Gallione CJ, Baldwin MA, Jackson CE,  Endoglin, a TGF-\u03b2 binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet. 1994;8(4):345\u2013351.789448410.1038\/ng1294-345"},{"issue":"2","key":"b5","series-title":"Nat Genet","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1038\/ng0696-189","article-title":"Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2","volume":"13","author":"Johnson DW","year":"1996","unstructured":"Johnson DW, Berg JN, Baldwin MA, Gallione CJ, Marondel I, Yoon SJ,  Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet. 1996;13(2):189\u2013195.864022510.1038\/ng0696-189"},{"issue":"1","key":"b6","series-title":"Cell Res","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1038\/cr.2008.326","article-title":"TGF-beta signaling in vascular biology and dysfunction","volume":"19","author":"Goumans MJ","year":"2009","unstructured":"Goumans MJ, Liu Z, ten Dijke P. TGF-beta signaling in vascular biology and dysfunction. Cell Res. 2009;19(1):116\u2013127.1911499410.1038\/cr.2008.326"},{"issue":"6","key":"b7","series-title":"Proc Natl Acad Sci U S A","doi-asserted-by":"publisher","first-page":"2626","DOI":"10.1073\/pnas.97.6.2626","article-title":"Activin receptor-like kinase 1 modulates transforming growth factor-\u03b21 signaling in the regulation of angiogenesis","volume":"97","author":"Oh SP","year":"2000","unstructured":"Oh SP, Seki T, Goss KA, Imamura T, Yi Y, Donahoe PK,  Activin receptor-like kinase 1 modulates transforming growth factor-\u03b21 signaling in the regulation of angiogenesis. Proc Natl Acad Sci U S A. 2000;97(6):2626\u20132631.1071699310.1073\/pnas.97.6.2626"},{"issue":"10","key":"b8","series-title":"J Clin Invest","doi-asserted-by":"publisher","first-page":"1343","DOI":"10.1172\/JCI8088","article-title":"A murine model of hereditary hemorrhagic telangiectasia","volume":"104","author":"Bourdeau A","year":"1999","unstructured":"Bourdeau A, Dumont DJ, Letarte M. A murine model of hereditary hemorrhagic telangiectasia. J Clin Invest. 1999;104(10):1343\u20131351.1056229610.1172\/JCI8088"},{"issue":"5419","key":"b9","series-title":"Science","doi-asserted-by":"publisher","first-page":"1534","DOI":"10.1126\/science.284.5419.1534","article-title":"Defective angiogenesis in mice lacking endoglin","volume":"284","author":"Li DY","year":"1999","unstructured":"Li DY, Sorensen LK, Brooke BS, Urness LD, Davis EC, Taylor DG,  Defective angiogenesis in mice lacking endoglin. Science. 1999;284(5419):1534\u20131537.1034874210.1126\/science.284.5419.1534"},{"issue":"1","key":"b10","series-title":"Dev Biol","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1006\/dbio.1999.9534","article-title":"Endoglin, an ancillary TGF\u03b2 receptor, is required for extraembryonic angiogenesis and plays a key role in heart development","volume":"217","author":"Arthur HM","year":"2000","unstructured":"Arthur HM, Ure J, Smith AJ, Renforth G, Wilson DI, Torsney E,  Endoglin, an ancillary TGF\u03b2 receptor, is required for extraembryonic angiogenesis and plays a key role in heart development. Dev Biol. 2000;217(1):42\u201353.10.1006\/dbio.1999.9534"},{"issue":"3","key":"b11","series-title":"Transl Stroke Res","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1007\/s12975-010-0020-x","article-title":"VEGF induces more severe cerebrovascular dysplasia in endoglin than in Alk1 mice","volume":"1","author":"Hao Q","year":"2010","unstructured":"Hao Q, Zhu Y, Su H, Shen F, Yang GY, Kim H, Young WL. VEGF induces more severe cerebrovascular dysplasia in endoglin than in Alk1 mice. Transl Stroke Res. 2010;1(3):197\u2013201.2064003510.1007\/s12975-010-0020-x"},{"issue":"5","key":"b12","series-title":"Stroke","doi-asserted-by":"publisher","first-page":"1432","DOI":"10.1161\/STROKEAHA.111.647024","article-title":"Age-dependent lethality in novel transgenic mouse models of central nervous system arteriovenous malformations","volume":"43","author":"Milton I","year":"2012","unstructured":"Milton I, Ouyang D, Allen CJ, Yanasak NE, Gossage JR, Alleyne CH Jr, Seki T. Age-dependent lethality in novel transgenic mouse models of central nervous system arteriovenous malformations. Stroke. 2012;43(5):1432\u20131435.2232855310.1161\/STROKEAHA.111.647024"},{"issue":"2","key":"b13","series-title":"Blood","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1182\/blood-2007-08-107359","article-title":"ALK5- and TGFBR2-independent role of ALK1 in the pathogenesis of hereditary hemorrhagic telangiectasia type 2","volume":"111","author":"Park SO","year":"2008","unstructured":"Park SO, Lee YJ, Seki T, Hong KH, Fliess N, Jiang Z,  ALK5- and TGFBR2-independent role of ALK1 in the pathogenesis of hereditary hemorrhagic telangiectasia type 2. Blood. 2008;111(2):633\u2013642.1791138410.1182\/blood-2007-08-107359"},{"issue":"4","key":"b14","series-title":"Angiogenesis","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1007\/s10456-014-9436-3","article-title":"VEGF neutralization can prevent and normalize arteriovenous malformations in an animal model for hereditary hemorrhagic telangiectasia 2","volume":"17","author":"Han C","year":"2014","unstructured":"Han C, Choe SW, Kim YH, Acharya AP, Keselowsky BG, Sorg BS,  VEGF neutralization can prevent and normalize arteriovenous malformations in an animal model for hereditary hemorrhagic telangiectasia 2. Angiogenesis. 2014;17(4):823\u2013830.10.1007\/s10456-014-9436-3"},{"issue":"11","key":"b15","series-title":"J Clin Invest","first-page":"3487","article-title":"Real-time imaging of de novo arteriovenous malformation in a mouse model of hereditary hemorrhagic telangiectasia","volume":"119","author":"Park SO","year":"2009","unstructured":"Park SO, Wankhede M, Lee YJ, Choi EJ, Fliess N, Choe SW,  Real-time imaging of de novo arteriovenous malformation in a mouse model of hereditary hemorrhagic telangiectasia. J Clin Invest. 2009;119(11):3487\u20133496."},{"issue":"10","key":"b16","series-title":"Proc Natl Acad Sci U S A","doi-asserted-by":"publisher","first-page":"7142","DOI":"10.1073\/pnas.102650499","article-title":"Smooth muscle-selective deletion of guanylyl cyclase-A prevents the acute but not chronic effects of ANP on blood pressure","volume":"99","author":"Holtwick R","year":"2002","unstructured":"Holtwick R, Gotthardt M, Skryabin B, Steinmetz M, Potthast R, Zetsche B,  Smooth muscle-selective deletion of guanylyl cyclase-A prevents the acute but not chronic effects of ANP on blood pressure. Proc Natl Acad Sci U S A. 2002;99(10):7142\u20137147.10.1073\/pnas.102650499"},{"issue":"10","key":"b17","series-title":"Arterioscler Thromb Vasc Biol","doi-asserted-by":"publisher","first-page":"2232","DOI":"10.1161\/ATVBAHA.114.303984","article-title":"Common and distinctive pathogenetic features of arteriovenous malformations in hereditary hemorrhagic telangiectasia 1 and hereditary hemorrhagic telangiectasia 2 animal models\u2014brief report","volume":"34","author":"Garrido-Martin EM","year":"2014","unstructured":"Garrido-Martin EM, Nguyen HL, Cunningham TA, Choe SW, Jiang Z, Arthur HM,  Common and distinctive pathogenetic features of arteriovenous malformations in hereditary hemorrhagic telangiectasia 1 and hereditary hemorrhagic telangiectasia 2 animal models\u2014brief report. Arterioscler Thromb Vasc Biol. 2014;34(10):2232\u20132236.2508222910.1161\/ATVBAHA.114.303984"},{"issue":"9412","key":"b18","series-title":"Lancet","doi-asserted-by":"publisher","first-page":"852","DOI":"10.1016\/S0140-6736(04)15732-2","article-title":"A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4)","volume":"363","author":"Gallione CJ","year":"2004","unstructured":"Gallione CJ, Repetto GM, Legius E, Rustgi AK, Schelley SL, Tejpar S,  A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet. 2004;363(9412):852\u2013859.1503103010.1016\/S0140-6736(04)15732-2"},{"issue":"14","key":"b19","series-title":"N Engl J Med","doi-asserted-by":"publisher","first-page":"918","DOI":"10.1056\/NEJM199510053331407","article-title":"Hereditary hemorrhagic telangiectasia","volume":"333","author":"Guttmacher AE","year":"1995","unstructured":"Guttmacher AE, Marchuk DA, White RI Jr. Hereditary hemorrhagic telangiectasia. N Engl J Med. 1995;333(14):918\u2013924.766687910.1056\/NEJM199510053331407"},{"issue":"7","key":"b20","series-title":"Eur J Hum Genet","doi-asserted-by":"publisher","first-page":"860","DOI":"10.1038\/ejhg.2009.35","article-title":"Hereditary haemorrhagic telangiectasia: a clinical and scientific review","volume":"17","author":"Govani FS","year":"2009","unstructured":"Govani FS, Shovlin CL. Hereditary haemorrhagic telangiectasia: a clinical and scientific review. Eur J Hum Genet. 2009;17(7):860\u2013871.1933731310.1038\/ejhg.2009.35"},{"issue":"5","key":"b21","series-title":"AJNR Am J Neuroradiol","doi-asserted-by":"publisher","first-page":"863","DOI":"10.3174\/ajnr.A4210","article-title":"Neurovascular manifestations in hereditary hemorrhagic telangiectasia: imaging features and genotype-phenotype correlations","volume":"36","author":"Krings T","year":"2015","unstructured":"Krings T, Kim H, Power S, Nelson J, Faughnan ME, Young WL, terBrugge KG. Neurovascular manifestations in hereditary hemorrhagic telangiectasia: imaging features and genotype-phenotype correlations. AJNR Am J Neuroradiol. 2015;36(5):863\u2013870.2557295210.3174\/ajnr.A4210"},{"issue":"4","key":"b22","series-title":"J Neurosurg","doi-asserted-by":"publisher","first-page":"476","DOI":"10.3171\/jns.1986.65.4.0476","article-title":"A proposed grading system for arteriovenous malformations","volume":"65","author":"Spetzler RF","year":"1986","unstructured":"Spetzler RF, Martin NA. A proposed grading system for arteriovenous malformations. J Neurosurg. 1986;65(4):476\u2013483.376095610.3171\/jns.1986.65.4.0476"},{"issue":"4","key":"b23","series-title":"Neurosurgery","doi-asserted-by":"publisher","first-page":"702","DOI":"10.1227\/01.NEU.0000367555.16733.E1","article-title":"A supplementary grading scale for selecting patients with brain arteriovenous malformations for surgery","volume":"66","author":"Lawton MT","year":"2010","unstructured":"Lawton MT, Kim H, McCulloch CE, Mikhak B, Young WL. A supplementary grading scale for selecting patients with brain arteriovenous malformations for surgery. Neurosurgery. 2010;66(4):702\u2013713.2019066610.1227\/01.NEU.0000367555.16733.E1"},{"issue":"1","key":"b24","series-title":"Indian J Radiol Imaging","doi-asserted-by":"publisher","first-page":"43","DOI":"10.4103\/0971-3026.45344","article-title":"Intracranial dural arteriovenous fistulas: a review","volume":"19","author":"Gupta A","year":"2009","unstructured":"Gupta A, Periakaruppan A. Intracranial dural arteriovenous fistulas: a review. Indian J Radiol Imaging. 2009;19(1):43\u201348.1977413910.4103\/0971-3026.45344"},{"issue":"5","key":"b25","series-title":"J Neurosurg","doi-asserted-by":"publisher","first-page":"884","DOI":"10.3171\/jns.1994.80.5.0884","article-title":"Development of acquired arteriovenous fistulas in rats due to venous hypertension","volume":"80","author":"Terada T","year":"1994","unstructured":"Terada T, Higashida RT, Halbach VV, Dowd CF, Tsuura M, Komai N,  Development of acquired arteriovenous fistulas in rats due to venous hypertension. J Neurosurg. 1994;80(5):884\u2013889.816962910.3171\/jns.1994.80.5.0884"},{"issue":"3","key":"b26","series-title":"J Neurosurg","doi-asserted-by":"publisher","first-page":"539","DOI":"10.3171\/jns.1995.83.3.0539","article-title":"Genesis of a dural arteriovenous malformation in a rat model","volume":"83","author":"Herman JM","year":"1995","unstructured":"Herman JM, Spetzler RF, Bederson JB, Kurbat JM, Zabramski JM. Genesis of a dural arteriovenous malformation in a rat model. J Neurosurg. 1995;83(3):539\u2013545.10.3171\/jns.1995.83.3.0539"},{"issue":"3","key":"b27","series-title":"Neurosurgery","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1227\/01.NEU.0000228962.68204.CF","article-title":"Expression of hypoxia-inducible factor-1 and vascular endothelial growth factor in response to venous hypertension","volume":"59","author":"Zhu Y","year":"2006","unstructured":"Zhu Y, Lawton MT, Du R, Shwe Y, Chen Y, Shen F,  Expression of hypoxia-inducible factor-1 and vascular endothelial growth factor in response to venous hypertension. Neurosurgery. 2006;59(3):687\u2013696.1695505110.1227\/01.NEU.0000228962.68204.CF"},{"issue":"6","key":"b28","series-title":"Ann Neurol","doi-asserted-by":"publisher","first-page":"954","DOI":"10.1002\/ana.22348","article-title":"Arteriovenous malformation in the adult mouse brain resembling the human disease","volume":"69","author":"Walker EJ","year":"2011","unstructured":"Walker EJ, Su H, Shen F, Choi EJ, Oh SP, Chen G,  Arteriovenous malformation in the adult mouse brain resembling the human disease. Ann Neurol. 2011;69(6):954\u2013962.2143793110.1002\/ana.22348"},{"key":"b29","series-title":"Acta Neurochir Suppl (Wien)","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1007\/978-3-7091-0693-8_14","article-title":"Brain arteriovenous malformation pathogenesis: a response-to-injury paradigm","volume":"111","author":"Kim H","year":"2011","unstructured":"Kim H, Su H, Weinsheimer S, Pawlikowska L, Young WL. Brain arteriovenous malformation pathogenesis: a response-to-injury paradigm. Acta Neurochir Suppl (Wien).2011;111:83\u201392.10.1007\/978-3-7091-0693-8_14"},{"issue":"5","key":"b30","series-title":"Stroke","doi-asserted-by":"publisher","first-page":"1362","DOI":"10.1161\/STROKEAHA.114.007367","article-title":"Hemorrhage rates from brain arteriovenous malformation in patients with hereditary hemorrhagic telangiectasia","volume":"46","author":"Kim H","year":"2015","unstructured":"Kim H, Nelson J, Krings T, terBrugge KG, McCulloch CE, Lawton MT,  Hemorrhage rates from brain arteriovenous malformation in patients with hereditary hemorrhagic telangiectasia. Stroke. 2015;46(5):1362\u20131364.2585823610.1161\/STROKEAHA.114.007367"},{"issue":"9917","key":"b31","series-title":"Lancet","doi-asserted-by":"publisher","first-page":"614","DOI":"10.1016\/S0140-6736(13)62302-8","article-title":"Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial","volume":"383","author":"Mohr JP","year":"2014","unstructured":"Mohr JP, Parides MK, Stapf C, Moquete E, Moy CS, Overbey JR,  Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial. Lancet. 2014;383(9917):614\u2013621.10.1016\/S0140-6736(13)62302-8"},{"issue":"5","key":"b32","series-title":"Stroke","doi-asserted-by":"publisher","first-page":"1240","DOI":"10.1161\/STROKEAHA.111.647263","article-title":"Silent intralesional microhemorrhage as a risk factor for brain arteriovenous malformation rupture","volume":"43","author":"Guo Y","year":"2012","unstructured":"Guo Y, Saunders T, Su H, Kim H, Akkoc D, Saloner DA,  Silent intralesional microhemorrhage as a risk factor for brain arteriovenous malformation rupture. Stroke. 2012;43(5):1240\u20131246.2230825310.1161\/STROKEAHA.111.647263"},{"issue":"5","key":"b33","series-title":"Neurosurgery","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1227\/NEU.0000000000000686","article-title":"Silent arteriovenous malformation hemorrhage and the recognition of \"unruptured\" arteriovenous malformation patients who benefit from surgical intervention","volume":"76","author":"Abla AA","year":"2015","unstructured":"Abla AA, Nelson J, Kim H, Hess CP, Tihan T, Lawton MT. Silent arteriovenous malformation hemorrhage and the recognition of \"unruptured\" arteriovenous malformation patients who benefit from surgical intervention. Neurosurgery. 2015;76(5):592\u2013600.2571451410.1227\/NEU.0000000000000686"},{"issue":"3","key":"b34","series-title":"Case report. J Neurosurg","first-page":"470","article-title":"Growth and regression of arteriovenous malformations in a patient with hereditary hemorrhagic telangiectasia","volume":"106","author":"Du R","year":"2007","unstructured":"Du R, Hashimoto T, Tihan T, Young WL, Perry V, Lawton MT. Growth and regression of arteriovenous malformations in a patient with hereditary hemorrhagic telangiectasia. Case report. J Neurosurg. 2007;106(3):470\u2013477."},{"issue":"6","key":"b35","series-title":"Neurosurgery","doi-asserted-by":"publisher","first-page":"1463","DOI":"10.1227\/01.NEU.0000125004.89129.B9","article-title":"The transgenic arteriovenous fistula in the rat: an experimental model of gene therapy for brain arteriovenous malformations","volume":"54","author":"Lawton MT","year":"2004","unstructured":"Lawton MT, Stewart CL, Wulfstat AA, Derugin N, Hashimoto T, Young WL. The transgenic arteriovenous fistula in the rat: an experimental model of gene therapy for brain arteriovenous malformations. Neurosurgery. 2004;54(6):1463\u20131471.1515730410.1227\/01.NEU.0000125004.89129.B9"},{"issue":"117","key":"b36","series-title":"Sci Transl Med","doi-asserted-by":"publisher","first-page":"117ra8","DOI":"10.1126\/scitranslmed.3002670","article-title":"Notch4 normalization reduces blood vessel size in arteriovenous malformations","volume":"4","author":"Murphy PA","year":"2012","unstructured":"Murphy PA, Kim TN, Lu G, Bollen AW, Schaffer CB, Wang RA. Notch4 normalization reduces blood vessel size in arteriovenous malformations. Sci Transl Med. 2012;4(117):117ra8.2226103210.1126\/scitranslmed.3002670"},{"issue":"2","key":"b37","series-title":"J Neurosurg","doi-asserted-by":"publisher","first-page":"302","DOI":"10.3171\/2016.7.JNS16847","article-title":"Prevalence and characteristics of brain arteriovenous malformations in hereditary hemorrhagic telangiectasia: a systematic review and meta-analysis","volume":"127","author":"Brinjikji W","year":"2017","unstructured":"Brinjikji W, Iyer VN, Wood CP, Lanzino G. Prevalence and characteristics of brain arteriovenous malformations in hereditary hemorrhagic telangiectasia: a systematic review and meta-analysis. J Neurosurg. 2017;127(2):302\u2013310.2776740410.3171\/2016.7.JNS16847"},{"issue":"3","key":"b38","series-title":"N Engl J Med","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1056\/NEJMoa1709449","article-title":"Somatic activating KRAS mutations in arteriovenous malformations of the brain","volume":"378","author":"Nikolaev SI","year":"2018","unstructured":"Nikolaev SI, Vetiska S, Bonilla X, Boudreau E, Jauhiainen S, Rezai Jahromi B,  Somatic activating KRAS mutations in arteriovenous malformations of the brain. N Engl J Med. 2018;378(3):250\u2013261.2929811610.1056\/NEJMoa1709449"},{"issue":"1","key":"b39","series-title":"Brain","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1093\/brain\/awy307","article-title":"High prevalence of KRAS\/BRAF somatic mutations in brain and spinal cord arteriovenous malformations","volume":"142","author":"Hong T","year":"2019","unstructured":"Hong T, Yan Y, Li J, Radovanovic I, Ma X, Shao YW,  High prevalence of KRAS\/BRAF somatic mutations in brain and spinal cord arteriovenous malformations. Brain. 2019;142(1):23\u201334.3054417710.1093\/brain\/awy307"},{"key":"b40","series-title":"World Neurosurg","doi-asserted-by":"publisher","first-page":"e1365","DOI":"10.1016\/j.wneu.2019.03.105","article-title":"KRAS G12D or G12V mutation in human brain arteriovenous malformations","volume":"126","author":"Oka M","year":"2019","unstructured":"Oka M, Kushamae M, Aoki T, Yamaguchi T, Kitazato K, Abekura Y,  KRAS G12D or G12V mutation in human brain arteriovenous malformations. World Neurosurg. 2019;126:e1365\u2013e1373.10.1016\/j.wneu.2019.03.105"},{"issue":"12","key":"b41","series-title":"PLoS One","doi-asserted-by":"publisher","first-page":"e0226852","DOI":"10.1371\/journal.pone.0226852","article-title":"Somatic mutations in intracranial arteriovenous malformations","volume":"14","author":"Goss JA","year":"2019","unstructured":"Goss JA, Huang AY, Smith E, Konczyk DJ, Smits PJ, Sudduth CL,  Somatic mutations in intracranial arteriovenous malformations. PLoS One. 2019;14(12):e0226852.3189162710.1371\/journal.pone.0226852"},{"key":"b42","series-title":"Hum Pathol","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.humpath.2019.04.004","article-title":"Activating KRAS mutations in arteriovenous malformations of the brain: frequency and clinicopathologic correlation","volume":"89","author":"Priemer DS","year":"2019","unstructured":"Priemer DS, Vortmeyer AO, Zhang S, Chang HY, Curless KL, Cheng L. Activating KRAS mutations in arteriovenous malformations of the brain: frequency and clinicopathologic correlation. Hum Pathol. 2019;89:33\u201339.3102647210.1016\/j.humpath.2019.04.004"},{"issue":"6","key":"b43","series-title":"Circ Res","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1161\/CIRCRESAHA.119.316500","article-title":"Somatic gain of KRAS function in the endothelium is sufficient to cause vascular malformations that require MEK but not PI3K signaling","volume":"127","author":"Fish JE","year":"2020","unstructured":"Fish JE, Flores Suarez CP, Boudreau E, Herman AM, Gutierrez MC, Gustafson D,  Somatic gain of KRAS function in the endothelium is sufficient to cause vascular malformations that require MEK but not PI3K signaling. Circ Res. 2020;127(6):727\u2013743.10.1161\/CIRCRESAHA.119.316500"},{"issue":"2","key":"b44","series-title":"PLoS One","doi-asserted-by":"publisher","first-page":"e88511","DOI":"10.1371\/journal.pone.0088511","article-title":"Novel brain arteriovenous malformation mouse models for type 1 hereditary hemorrhagic telangiectasia","volume":"9","author":"Choi EJ","year":"2014","unstructured":"Choi EJ, Chen W, Jun K, Arthur HM, Young WL, Su H. Novel brain arteriovenous malformation mouse models for type 1 hereditary hemorrhagic telangiectasia. PLoS One. 2014;9(2):e88511.2452039110.1371\/journal.pone.0088511"},{"issue":"2","key":"b45","series-title":"Arterioscler Thromb Vasc Biol","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1161\/ATVBAHA.112.300485","article-title":"Reduced mural cell coverage and impaired vessel integrity after angiogenic stimulation in the Alk1-deficient brain","volume":"33","author":"Chen W","year":"2013","unstructured":"Chen W, Guo Y, Walker EJ, Shen F, Jun K, Oh SP,  Reduced mural cell coverage and impaired vessel integrity after angiogenic stimulation in the Alk1-deficient brain. Arterioscler Thromb Vasc Biol. 2013;33(2):305\u2013310.2324140710.1161\/ATVBAHA.112.300485"},{"issue":"3","key":"b46","series-title":"Stroke","doi-asserted-by":"publisher","first-page":"900","DOI":"10.1161\/STROKEAHA.113.003655","article-title":"De novo cerebrovascular malformation in the adult mouse after endothelial Alk1 deletion and angiogenic stimulation","volume":"45","author":"Chen W","year":"2014","unstructured":"Chen W, Sun Z, Han Z, Jun K, Camus M, Wankhede M,  De novo cerebrovascular malformation in the adult mouse after endothelial Alk1 deletion and angiogenic stimulation. Stroke. 2014;45(3):900\u2013902.2445729310.1161\/STROKEAHA.113.003655"},{"issue":"6","key":"b47","series-title":"Cerebrovasc Dis","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1159\/000337762","article-title":"Minimal homozygous endothelial deletion of Eng with VEGF stimulation is sufficient to cause cerebrovascular dysplasia in the adult mouse","volume":"33","author":"Choi EJ","year":"2012","unstructured":"Choi EJ, Walker EJ, Shen F, Oh SP, Arthur HM, Young WL, Su H. Minimal homozygous endothelial deletion of Eng with VEGF stimulation is sufficient to cause cerebrovascular dysplasia in the adult mouse. Cerebrovasc Dis. 2012;33(6):540\u2013547.2257195810.1159\/000337762"}],"container-title":["Journal of Neurosurgery"],"original-title":[],"link":[{"URL":"https:\/\/thejns.org\/view\/journals\/j-neurosurg\/137\/1\/article-p163.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/thejns.org\/downloadpdf\/journals\/j-neurosurg\/137\/1\/article-p163.xml","content-type":"text\/html","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/thejns.org\/downloadpdf\/journals\/j-neurosurg\/137\/1\/article-p163.xml","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,18]],"date-time":"2024-05-18T11:05:42Z","timestamp":1716030342000},"score":1,"resource":{"primary":{"URL":"https:\/\/thejns.org\/view\/journals\/j-neurosurg\/137\/1\/article-p163.xml"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,1]]},"references-count":47,"journal-issue":{"issue":"1"},"URL":"https:\/\/doi.org\/10.3171\/2021.6.jns21717","relation":{},"ISSN":["0022-3085","1933-0693"],"issn-type":[{"value":"0022-3085","type":"print"},{"value":"1933-0693","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,1]]}}}