AccScience Publishing / GPD / Volume 2 / Issue 2 / DOI: 10.36922/gpd.0312
Cite this article
90
Download
1323
Views
Journal Browser
Volume | Year
Issue
Search
News and Announcements
View All
ORIGINAL RESEARCH ARTICLE

An updated review on the genetics of arteriovenous malformations

Krisna Maddy1 Anjalika Chalamgari1 Ogechukwu Ariwodo1 Zhuri Nisseau-Bey1 Justin Maldonado1 Brandon Lucke-Wold1*
Show Less
1 Department of Neurosurgery, University of Florida, Gainesville, Florida, USA
Submitted: 3 March 2023 | Accepted: 7 June 2023 | Published: 26 June 2023
© 2023 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
Abstract

Arteriovenous malformations (AVM) are congenital malformations of the cerebral vasculature resulting in pathological shunting of blood through dilated arteries and veins. The most common clinical manifestations of AVM are intracerebral hemorrhage, due to rupture of these lesions as they continue to expand, which can have devastating neurological consequences and residual deficits. The genetic underpinnings of AVM have been explored for their role in the angiogenesis of these lesions in both its sporadic and inherited forms. In recent times, our understanding of the genetic variation involved in the pathogenesis AVM has advanced in both the preclinical and clinical realms. The current review highlights in detail these advancements, namely, the genetic underpinnings of diagnostic testing and profiling of AVM, and the preclinical epigenetic and genetic data on AVM pathogenesis and growth. In addition, we review the current candidate genes implicated in AVM pathogenesis in the literature. Finally, we provide a discussion on the genetic conditions associated with AVM and the advancements in treatment paradigms influenced by the genetic profiles of these lesions.

Keywords
Arteriovenous malformations
Intracerebral hemorrhage
Genetics
Capillary malformations
Funding
None.
References
  1. Chen CJ, Ding D, Derdeyn C, et al., 2020, Brain arteriovenous malformations: A review of natural history, pathobiology, and interventions. Neurology, 95(20): 917–927. https://doi.org/10.1212/WNL.0000000000010968

 

  1. Schimmel K, Ali MK, Tan SY, et al., 2021, Arteriovenous malformations-current understanding of the pathogenesis with implications for treatment. Int J Mol Sci, 22(16): 9037. https://doi.org/10.3390/ijms22169037

 

  1. Daou BJ, Palmateer G, Thompson BG, et al., 2020, Stereotactic radiosurgery for brain arteriovenous malformations: Evaluation of obliteration and review of associated predictors. J Stroke Cerebrovasc Dis, 29(8): 104863. https://doi.org/10.1016/j.jstrokecerebrovasdis.2020.104863

 

  1. Moon K, Levitt MR, Almefty RO, et al., 2015, Safety and efficacy of surgical resection of unruptured low-grade arteriovenous malformations from the modern decade. Neurosurgery, 77(6): 948–953. https://doi.org/10.1227/NEU.0000000000000968

 

  1. Xiaochuan H, Yuhua J, Xianli L, et al., 2015, Targeted embolization reduces hemorrhage complications in partially embolized cerebral AVM combined with gamma knife surgery. Interv Neuroradiol, 21(1): 80–87. https://doi.org/10.15274/INR-2014-10090

 

  1. 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. https://doi.org/10.1007/978-3-211-09469-3_38

 

  1. Rangel-Castilla L, Russin JJ, Martinez-del-Campo E, et al., 2014, Molecular and cellular biology of cerebral arteriovenous malformations: A review of current concepts and future trends in treatment. Neurosurg Focus, 37(3): E1. https://doi.org/10.3171/2014.7.FOCUS14214

 

  1. Shenkar R, Elliott JP, Diener K, et al., 2003, Differential gene expression in human cerebrovascular malformations. Neurosurgery, 52(2): 465–478. https://doi.org/10.1227/01.NEU.0000044131.03495.22

 

  1. Shaligram SS, Winkler E, Cooke D, et al., 2019, Risk factors for hemorrhage of brain arteriovenous malformation. CNS Neurosci Ther, 25(10): 1085–1095. https://doi.org/10.1111/cns.13200

 

  1. Begbie ME, Wallace GM, Shovlin CL, 2003, Hereditary haemorrhagic telangiectasia (Osler-Weber-Rendu syndrome): A view from the 21st century. Postgrad Med J, 79(927): 18–24. https://doi.org/10.1136/pmj.79.927.18

 

  1. Solomon RA, Connolly ES Jr., 2017, Arteriovenous malformations of the brain. N Engl J Med, 376(19): 1859–1866. https://doi.org/10.1056/NEJMra1607407

 

  1. Osbun JW, Reynolds MR, Barrow DL, 2017, Arteriovenous malformations. Handb Clin Neurol, 143: 25–29. https://doi.org/10.1016/B978-0-444-63640-9.00003-5

 

  1. Ferrara AR, 2011, Brain arteriovenous malformations. Radiol Technol, 82(6): 543MR–56MR.

 

  1. Delev D, Pavlova A, Grote A, et al., 2017, NOTCH4 gene polymorphisms as potential risk factors for brain arteriovenous malformation development and hemorrhagic presentation. J Neurosurg, 126(5): 1552–1559. https://doi.org/10.3171/2016.3.JNS151731

 

  1. Krithika S, Sumi S, 2021, Neurovascular inflammation in the pathogenesis of brain arteriovenous malformations. J Cell Physiol, 236(7): 4841–4856. https://doi.org/10.1002/jcp.30226

 

  1. Do Prado LB, Han C, Oh SP, et al., 2019, Recent advances in basic research for brain arteriovenous malformation. Int J Mol Sci, 20(21): 5324. https://doi.org/10.3390/ijms20215324

 

  1. Greenberg MS, editor, 2010, Handbook of Neurosurgery. 7th ed. United States: Thieme Medical Publishers.

 

  1. Rutledge WC, Ko NU, Lawton MT, et al., 2014, Hemorrhage rates and risk factors in the natural history course of brain arteriovenous malformations. Transl Stroke Res, 5(5): 538–542. https://doi.org/10.1007/s12975-014-0351-0

 

  1. Da Costa L, Wallace MC, Ter Brugge KG, et al., 2009, The natural history and predictive features of hemorrhage from brain arteriovenous malformations. Stroke, 40(1): 100–105. https://doi.org/10.1161/STROKEAHA.108.524678

 

  1. El-Abtah ME, Petitt JC, Kashkoush A, et al., 2022, Endovascular management of arteriovenous malformation-associated intracranial aneurysms: A systematic literature review. World Neurosurg, 164: 257–269. https://doi.org/10.1016/j.wneu.2022.05.051

 

  1. Gross BA, Du R, 2013, Natural history of cerebral arteriovenous malformations: A meta-analysis: Clinical article. J Neurosurg, 118(2): 437–443. https://doi.org/10.3171/2012.10.JNS121280

 

  1. Stapf C, Mohr JP, Pile-Spellman J, et al., 2002, Concurrent arterial aneurysms in brain arteriovenous malformations with haemorrhagic presentation. J Neurol Neurosurg Psychiatry, 73(3): 294–298. https://doi.org/10.1136/jnnp.73.3.294

 

  1. Mullan S, 1994, Reflections upon the nature and management of intracranial and intraspinal vascular malformations and fistulae. J Neurosurg, 80(4): 606–616. https://doi.org/10.3171/jns.1994.80.4.0606

 

  1. Zafar A, Fiani B, Hadi H, et al., 2020, Cerebral vascular malformations and their imaging modalities. Neurol Sci, 41(9): 2407–2421. https://doi.org/10.1007/s10072-020-04415-4

 

  1. Meybodi AT, Lawton MT, 2020, Modern radiosurgical and endovascular classification schemes for brain arteriovenous malformations. Neurosurg Rev, 43(1): 49–58. https://doi.org/10.1007/s10143-018-0983-8

 

  1. Pollock BE, Storlie CB, Link MJ, et al., 2017, Comparative analysis of arteriovenous malformation grading scales in predicting outcomes after stereotactic radiosurgery. J Neurosurg, 126(3): 852–858. https://doi.org/10.3171/2015.11.JNS151300

 

  1. Jin H, Jiang Y, Ge H, et al., 2017, Comparison of grading scales regarding perioperative complications and clinical outcomes of brain arteriovenous malformations after endovascular therapy-multicenter study. World Neurosurg, 106: 394–401. https://doi.org/10.1016/j.wneu.2017.07.020

 

  1. Komiyama M, 2016, Pathogenesis of brain arteriovenous malformations. Neurol Med Chir (Tokyo), 56(6): 317–325. https://doi.org/10.2176/nmc.ra.2016-0051

 

  1. Chen Y, Zhu W, Bollen AW, et al., 2008, Evidence of inflammatory cell involvement in brain arteriovenous malformations. Neurosurgery, 62(6): 1340–1349; discussion 1349–1350. https://doi.org/10.1227/01.neu.0000333306.64683.b5

 

  1. 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. https://doi.org/10.1007/978-3-211-09469-3_38

 

  1. Mukhtarova K, Zholdybayeva E, Kairov U, et al., 2022, Whole-exome sequencing reveals pathogenic SIRT1 variant in brain arteriovenous malformation: A case report. Genes, 13(10): 1689. https://doi.org/10.3390/genes13101689

 

  1. Yan D, Hao Q, Chen Y, et al., 2022, mTOR-FABP4 signal is activated in brain arteriovenous malformations in humans. J Mol Med Berl Ger, 100(9): 1287–1297. https://doi.org/10.1007/s00109-022-02237-9

 

  1. Bameri O, Salarzaei M, Parooie F, 2021, KRAS/BRAF mutations in brain arteriovenous malformations: A systematic review and meta-analysis. Interv Neuroradiol, 27(4): 539–546. https://doi.org/10.1177/1591019920982810

 

  1. Thomas JM, Surendran S, Abraham M, et al., 2016, Genetic and epigenetic mechanisms in the development of arteriovenous malformations in the brain. Clin Epigenetics, 8(1): 78. https://doi.org/10.1186/s13148-016-0248-8

 

  1. Scimone C, Donato L, Alafaci C, et al., 2020, High-throughput sequencing to detect novel likely gene-disrupting variants in pathogenesis of sporadic brain arteriovenous malformations. Front Genet, 11: 146. https://doi.org/10.3389/fgene.2020.00146

 

  1. Kim YH, Choi J, Yang MJ, et al., 2019, A MST1-FOXO1 cascade establishes endothelial tip cell polarity and facilitates sprouting angiogenesis. Nat Commun, 10(1): 838. https://doi.org/10.1038/s41467-019-08773-2

 

  1. Shoemaker LD, Fuentes LF, Santiago SM, et al., 2014, Human brain arteriovenous malformations express lymphatic-associated genes. Ann Clin Transl Neurol, 1(12): 982–995. https://doi.org/10.1002/acn3.142

 

  1. Winkler EA, Birk H, Burkhardt JK, et al., 2018, Reductions in brain pericytes are associated with arteriovenous malformation vascular instability. J Neurosurg, 129(6): 1464–1474. https://doi.org/10.3171/2017.6.JNS17860

 

  1. Scholz A, Plate KH, Reiss Y, 2015, Angiopoietin-2: A multifaceted cytokine that functions in both angiogenesis and inflammation. Ann N Y Acad Sci, 1347(1): 45–51. https://doi.org/10.1111/nyas.12726

 

  1. Chen Y, Li Z, Shi Y, et al., 2018, Deep sequencing of small RNAs in blood of patients with brain arteriovenous malformations. World Neurosurg, 115: e570–e579. https://doi.org/10.1016/j.wneu.2018.04.097

 

  1. Robert F, Desroches-Castan A, Bailly S, et al., 2020, Future treatments for hereditary hemorrhagic telangiectasia. Orphanet J Rare Dis, 15(1): 4. https://doi.org/10.1186/s13023-019-1281-4

 

  1. Hiltunen MO, Turunen MP, Hakkinen TP, et al., 2002, DNA hypomethylation and methyltransferase expression in atherosclerotic lesions. Vasc Med Lond Engl, 7(1): 5–11. https://doi.org/10.1191/1358863x02vm418oa

 

  1. Chan Y, Fish JE, D’Abreo C, et al., 2004, The cell-specific expression of endothelial nitric-oxide synthase: A role for DNA methylation. J Biol Chem, 279(33): 35087–35100. https://doi.org/10.1074/jbc.M405063200

 

  1. Rao X, Zhong J, Zhang S, et al., 2011, Loss of methyl-CpG-binding domain protein 2 enhances endothelial angiogenesis and protects mice against hind-limb ischemic injury. Circulation, 123(25): 2964–2974. https://doi.org/10.1161/CIRCULATIONAHA.110.966408

 

  1. Jiang YZ, Manduchi E, Jimenez JM, et al., 2015, Endothelial epigenetics in biomechanical stress: Disturbed flow-mediated epigenomic plasticity in vivo and in vitro. Arterioscler Thromb Vasc Biol, 35(6): 1317–1326. https://doi.org/10.1161/ATVBAHA.115.303427

 

  1. Lee DY, Lee CI, Lin TE, et al., 2012, Role of histone deacetylases in transcription factor regulation and cell cycle modulation in endothelial cells in response to disturbed flow. Proc Natl Acad Sci U S A, 109(6): 1967–1972. https://doi.org/10.1073/pnas.1121214109

 

  1. Mottet D, Bellahcene A, Pirotte S, et al., 2007, Histone deacetylase 7 silencing alters endothelial cell migration, a key step in angiogenesis. Circ Res, 101: 1237–1246.

 

  1. Cobb MH, 1999, MAP kinase pathways. Prog Biophys Mol Biol, 71(3–4): 479–500. https://doi.org/10.1016/S0079-6107(98)00056-X

 

  1. Fischer AM, Katayama CD, Pages G, et al., 2005, The role of Erk1 and Erk2 in multiple stages of T cell development. Immunity, 23(4): 431–443. https://doi.org/10.1016/j.immuni.2005.08.013

 

  1. Couto JA, Huang AY, Konczyk DJ, et al., 2017, Somatic MAP2K1 mutations are associated with extracranial arteriovenous malformation. Am J Hum Genet, 100(3): 546–554. https://doi.org/10.1016/j.ajhg.2017.01.018

 

  1. Smits PJ, Konczyk DJ, Sudduth CL, et al., 2020, Endothelial MAP2K1 mutations in arteriovenous malformation activate the RAS/MAPK pathway. Biochem Biophys Res Commun, 529(2): 450–454. https://doi.org/10.1016/j.bbrc.2020.06.022

 

  1. Revencu N, Boon LM, Mendola A, et al., 2013, RASA1 mutations and associated phenotypes in 68 families with capillary malformation-arteriovenous malformation. Hum Mutat, 34(12): 1632–1641. https://doi.org/10.1002/humu.22431

 

  1. Revencu N, Fastre E, Ravoet M, et al., 2020, RASA1 mosaic mutations in patients with capillary malformation-arteriovenous malformation. J Med Genet, 57(1): 48–52. https://doi.org/10.1136/jmedgenet-2019-106024

 

  1. Hongo H, Miyawaki S, Teranishi Y, et al., 2022, Genetics of brain arteriovenous malformations and cerebral cavernous malformations. J Hum Genet, 68: 157–167. https://doi.org/10.1038/s10038-022-01063-8

 

  1. Lapinski PE, Doosti A, Salato V, et al., 2018, Somatic second hit mutation of RASA1 in vascular endothelial cells in capillary malformation-arteriovenous malformation. Eur J Med Genetm, 61(1): 11–16. https://doi.org/10.1016/j.ejmg.2017.10.004

 

  1. Wolf K, Hu H, Isaji T, et al., 2019, Molecular identity of arteries, veins, and lymphatics. J Vasc Surg, 69(1): 253–262. https://doi.org/10.1016/j.jvs.2018.06.195

 

  1. Himanen JP, 2012, Ectodomain structures of Eph receptors. Semin Cell Dev Biol, 23(1): 35–42. https://doi.org/10.1016/j.semcdb.2011.10.025

 

  1. Eilken HM, Adams RH, 2010, Dynamics of endothelial cell behavior in sprouting angiogenesis. Curr Opin Cell Biol, 22(5): 617–625. https://doi.org/10.1016/j.ceb.2010.08.010

 

  1. Choi EJ, Chen W, Jun K, et al., 2014, Novel brain arteriovenous malformation mouse models for Type 1 hereditary hemorrhagic telangiectasia. PLoS One, 9(2): e88511. https://doi.org/10.1371/journal.pone.0088511

 

  1. Rossi E, Bernabeu C, Smadja DM, 2019, Endoglin as an adhesion molecule in mature and progenitor endothelial cells: A function beyond TGF-β. Front Med, 6: 10. https://doi.org/10.3389/fmed.2019.00010

 

  1. Wooderchak-Donahue WL, McDonald J, O’Fallon B, et al., 2013, BMP9 mutations cause a vascular-anomaly syndrome with phenotypic overlap with hereditary hemorrhagic telangiectasia. Am J Hum Genet, 93(3): 530–537. https://doi.org/10.1016/j.ajhg.2013.07.004

 

  1. Hodgson J, Ruiz-Llorente L, McDonald J, et al., 2021, Homozygous GDF2 nonsense mutations result in a loss of circulating BMP9 and BMP10 and are associated with either PAH or an “HHT‐like” syndrome in children. Mol Genet Genomic Med, 9(12): e1685. https://doi.org/10.1002/mgg3.1685

 

  1. Balachandar S, Graves TJ, Shimonty A, et al., 2022, Identification and validation of a novel pathogenic variant in GDF2 (BMP9) responsible for hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations. Am J Med Genet A, 188(3): 959–964. https://doi.org/10.1002/ajmg.a.62584

 

  1. Farhan A, Yuan F, Partan E, et al., 2022, Clinical manifestations of patients with GDF2 mutations associated with hereditary hemorrhagic telangiectasia Type 5. Am J Med Genet A, 188(1): 199–209. https://doi.org/10.1002/ajmg.a.62522

 

  1. Gallione CJ, Richards JA, Letteboer TGW, et al., 2006, SMAD4 mutations found in unselected HHT patients. J Med Genet, 43(10): 793–797. https://doi.org/10.1136/jmg.2006.041517

 

  1. Wain KE, Ellingson MS, McDonald J, et al., 2014, Appreciating the broad clinical features of SMAD4 mutation carriers: A multicenter chart review. Genet Med, 16(8): 588–593. https://doi.org/10.1038/gim.2014.5

 

  1. Steiger HJ, 2021, Recent progress understanding pathophysiology and genesis of brain AVM-a narrative review. Neurosurg Rev, 44(6): 3165–3175. https://doi.org/10.1007/s10143-021-01526-0

 

  1. Nikolaev SI, Vetiska S, Bonilla X, et al., 2018, Somatic activating KRAS mutations in arteriovenous malformations of the brain. N Engl J Med, 378(3): 250–261. https://doi.org/10.1056/NEJMoa1709449

 

  1. Fish JE, Suarez CPF, Boudreau E, et al., 2020, Somatic gain of KRAS function in the endothelium is sufficient to cause vascular malformations that require MEK but not PI3K signaling. Circ Res, 127(6): 727–743. https://doi.org/10.1161/CIRCRESAHA.119.316500

 

  1. Oka M, Kushamae M, Aoki T, et al., 2019, KRAS G12D or G12V mutation in human brain arteriovenous malformations. World Neurosurg, 126: e1365–e1373. https://doi.org/10.1016/j.wneu.2019.03.105

 

  1. Al-Olabi L, Polubothu S, Dowsett K, et al., 2018, Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy. J Clin Invest, 128(4): 1496–1508. https://doi.org/10.1172/JCI98589

 

  1. Priemer DS, Vortmeyer AO, Zhang S, et al., 2019, Activating KRAS mutations in arteriovenous malformations of the brain: Frequency and clinicopathologic correlation. Hum Pathol, 89: 33–39. https://doi.org/10.1016/j.humpath.2019.04.004

 

  1. Hong T, Yan Y, Li J, et al., 2019, High prevalence of KRAS/BRAF somatic mutations in brain and spinal cord arteriovenous malformations. Brain, 142(1): 23–34. https://doi.org/10.1093/brain/awy307

 

  1. McCubrey JA, Steelman LS, Chappell WH, et al., 2007, Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta, 1773(8): 1263–1284. https://doi.org/10.1016/j.bbamcr.2006.10.001

 

  1. Whitehead KJ, Smith MCP, Li DY, 2013, Arteriovenous malformations and other vascular malformation syndromes. Cold Spring Harb Perspect Med, 3(2): a006635–a006635. https://doi.org/10.1101/cshperspect.a006635

 

  1. Mouchtouris N, Jabbour PM, Starke RM, et al., 2015, Biology of cerebral arteriovenous malformations with a focus on inflammation. J Cereb Blood Flow Metab, 35(2): 167–175. https://doi.org/10.1038/jcbfm.2014.179

 

  1. Sturiale CL, Puca A, Sebastiani P, et al., 2013, Single nucleotide polymorphisms associated with sporadic brain arteriovenous malformations: Where do we stand? Brain, 136(2): 665–681. https://doi.org/10.1093/brain/aws180

 

  1. Rosenberg GA, 2002, Matrix metalloproteinases in neuroinflammation. Glia, 39(3): 279–291.https://doi.org/10.1002/glia.10108

 

  1. Li H, Nam Y, Huo R, et al., 2021, De novo germline and somatic variants convergently promote endothelial-to mesenchymal transition in simplex brain arteriovenous malformation. Circ Res, 129(9): 825–839. https://doi.org/10.1161/CIRCRESAHA.121.319004

 

  1. Pawlikowska L, Tran MN, Achrol AS, et al., 2004, Polymorphisms in genes involved in inflammatory and angiogenic pathways and the risk of hemorrhagic presentation of brain arteriovenous malformations. Stroke, 35(10): 2294–2300. https://doi.org/10.1161/01.STR.0000141932.44613.b1

 

  1. Chen Y, Pawlikowska L, Yao JS, et al., 2006, Interleukin-6 involvement in brain arteriovenous malformations. Ann Neurol, 59(1): 72–80. https://doi.org/10.1002/ana.20697

 

  1. Pawlikowska L, Poon KYT, Achrol AS, et al., 2006, Apolipoprotein E ε2 is associated with new hemorrhage risk in brain arteriovenous malformations. Neurosurgery, 58(5): 838–843. https://doi.org/10.1227/01.NEU.0000209605.18358.E5

 

  1. Nishino K, Ito Y, Sorimachi T, et al., 2010, Sturge-Weber syndrome associated with arteriovenous malformation in a patient presenting with progressive brain edema and cyst formation. J Neurosurg Pediatr, 5(5): 529–534. https://doi.org/10.3171/2010.1.PEDS09140

 

  1. Higueros E, Roe E, Granell E, et al., 2017, Sturge-Weber syndrome: A review. Actas Dermosifiliogr, 108(5): 407–417. https://doi.org/10.1016/j.adengl.2017.03.034

 

  1. Yeom S, Comi AM, 2022, Updates on Sturge-Weber syndrome. Stroke, 53(12):3769–3779. https://doi.org/10.1161/STROKEAHA.122.038585

 

  1. Fukushima T, Hamano K, Shin K, et al., 1989, A case of multiple arteriovenous malformations and diffuse venous abnormalities with facial port-wine stain. Childs Nerv Syst, 5(2): 114–117. https://doi.org/10.1007/BF00571122

 

  1. Laufer L, Cohen A, 1994, Sturge-Weber syndrome associated with a large left hemispheric arteriovenous malformation. Pediatr Radiol, 24(4): 272–273. https://doi.org/10.1007/BF02015455

 

  1. Mizutani T, Tanaka H, Aruga T, 1992, Multiple arteriovenous malformations located in the cerebellum, posterior fossa, spinal cord, dura, and scalp with associated port-wine stain and supratentorial venous anomaly. Neurosurgery, 31(1): 137–140; discussion 140–141. https://doi.org/10.1227/00006123-199207000-00022

 

  1. Flieger D, Hainke S, Fischbach W, 2006, Dramatic improvement in hereditary hemorrhagic telangiectasia after treatment with the vascular endothelial growth factor (VEGF) antagonist bevacizumab. Ann Hematol, 85(9): 631–632. https://doi.org/10.1007/s00277-006-0147-8

 

  1. Mitchell A, Adams LA, MacQuillan G, et al., 2008, Bevacizumab reverses need for liver transplantation in hereditary hemorrhagic telangiectasia. Liver Transpl, 14(2): 210–213. https://doi.org/10.1002/lt.21417

 

  1. Dupuis-Girod S, Ginon I, Saurin JC, et al., 2012, Bevacizumab in patients with hereditary hemorrhagic telangiectasia and severe hepatic vascular malformations and high cardiacoutput. JAMA, 307(9):648–955. https://doi.org/10.1001/jama.2012.250

 

  1. Jabbour MN, Elder JB, Samuelson CG, et al., 2009, Aberrant angiogenic characteristics of human brain arteriovenous malformation endothelial cells. Neurosurgery, 64(1): 139–148. https://doi.org/10.1227/01.NEU.0000334417.56742.24

 

  1. Zhu W, Shen F, Mao L, et al., 2017, Soluble FLT1 gene therapy alleviates brain arteriovenous malformation severity. Stroke, 48(5): 1420–1423. https://doi.org/10.1161/STROKEAHA.116.015713

 

  1. Crist AM, Zhou X, Garai J, et al., 2019, Angiopoietin-2 inhibition rescues arteriovenous malformation in a Smad4 hereditary hemorrhagic telangiectasia mouse model. Circulation, 139(17): 2049–2063. https://doi.org/10.1161/CIRCULATIONAHA.118.036952

 

  1. Ola R, Dubrac A, Han J, et al., 2016, PI3 kinase inhibition improves vascular malformations in mouse models of hereditary haemorrhagic telangiectasia. Nat Commun, 7(1): 13650. https://doi.org/10.1038/ncomms13650

 

  1. Amyere M, Revencu N, Helaers R, et al., 2017, Germline loss-of-function mutations in EPHB4 cause a second form of capillary malformation-arteriovenous malformation (CM-AVM2) deregulating RAS-MAPK signaling. Circulation, 136(11): 1037–1048. https://doi.org/10.1161/CIRCULATIONAHA.116.026886

 

  1. McAllister KA, Grogg KM, Johnson DW, et al., 1994, Endoglin, a TGF-β binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia Type 1. Nat Genet, 8(4): 345–351. https://doi.org/10.1038/ng1294-345

 

  1. Ruiz S, Chandakkar P, Zhao H, et al., 2017, Tacrolimus rescues the signaling and gene expression signature of endothelial ALK1 loss-of-function and improves HHT vascular pathology. Hum Mol Genet, 26(24): 4786–4798. https://doi.org/10.1093/hmg/ddx358

 

  1. Ruiz S, Zhao H, Chandakkar P, et al., 2020, Correcting Smad1/5/8, mTOR, and VEGFR2 treats pathology in hereditary hemorrhagic telangiectasia models. J Clin Invest, 130(2): 942–957. https://doi.org/10.1172/JCI127425

 

  1. Al-Samkari H, Eng W, 2022, A precision medicine approach to hereditary hemorrhagic telangiectasia and complex vascular anomalies. J Thromb Haemost, 20(5): 1077–1088. https://doi.org/10.1111/jth.15715

 

  1. Nicholson CL, Flanagan S, Murati M, et al., 2022, Successful management of an arteriovenous malformation with trametinib in a patient with capillary-malformation arteriovenous malformation syndrome and cardiac compromise. Pediatr Dermatol, 39(2): 316–319. https://doi.org/10.1111/pde.14912

 

  1. Zhu W, Chen W, Zou D, et al., 2018, Thalidomide reduces hemorrhage of brain arteriovenous malformations in a mouse model. Stroke, 49(5): 1232–1240. https://doi.org/10.1161/STROKEAHA.117.020356

 

  1. Chen W, Guo Y, Walker EJ, et al., 13, Reduced mural cell coverage and impaired vessel integrity after angiogenic stimulation in the Alk1-deficient brain. Arterioscler Thromb Vasc Biol, 33(2): 305–310. https://doi.org/10.1161/ATVBAHA.112.300485

 

  1. McLaren O, Ronan N, 2019, Recurrent epistaxis in an adolescent. BMJ, 2019: l5393. https://doi.org/10.1136/bmj.l5393

 

  1. Agarwal N, Schalet G, Shah M, et al., 2012, Endovascular management of cerebral arteriovenous malformations in pregnancy: Two case reports and a review of the literature. J Neurol Res, 2: 215–220. https://doi.org/10.4021/jnr148w

 

  1. El Sissy FN, Wassef M, Faucon B, et al., 2022, Somatic mutational landscape of extracranial arteriovenous malformations and phenotypic correlations. J Eur Acad Dermatol Venereol, 36(6): 905–912. https://doi.org/10.1111/jdv.18046

 

  1. Ota T, Komiyama M, 2020, Pathogenesis of non-hereditary brain arteriovenous malformation and therapeutic implications. Interv Neuroradiol, 26(3): 244–253. https://doi.org/10.1177/1591019920901931

 

  1. Achrol AS, Pawlikowska L, McCulloch CE, et al., 2006, Tumor necrosis factor-α–238G>A promoter polymorphism is associated with increased risk of new hemorrhage in the natural course of patients with brain arteriovenous malformations. Stroke, 37(1): 231–234. https://doi.org/10.1161/01.STR.0000195133.98378.4b

 

  1. Kim H, Hysi PG, Pawlikowska L, et al., 2008, Population stratification in a case-control study of brain arteriovenous malformation in latinos. Neuroepidemiology, 31(4): 224–228. https://doi.org/10.1159/000160215

 

  1. Zhao Y, Li P, Fan W, et al., 2010, The rs522616 polymorphism in the matrix metalloproteinase-3 (MMP-3) gene is associated with sporadic brain arteriovenous malformation in a Chinese population. J Clin Neurosci, 17(12): 1568–1572. https://doi.org/10.1016/j.jocn.2010.04.023

 

  1. Fontanella M, Rubino E, Crobeddu E, et al., 2012, Brain arteriovenous malformations are associated with interleukin-1 cluster gene polymorphisms. Neurosurgery, 70(1): 12–17. https://doi.org/10.1227/NEU.0b013e31822d9881

 

  1. Kim H, Hysi PG, Pawlikowska L, et al., 2009, Common variants in interleukin-1-beta gene are associated with intracranial hemorrhage and susceptibility to brain arteriovenous malformation. Cerebrovasc Dis, 27(2): 176–182. https://doi.org/10.1159/000185609

 

  1. Song M, Bai H, Zhang P, et al., 2023, Promising applications of human-derived saliva biomarker testing in clinical diagnostics. Int J Oral Sci, 15(1): 2. https://doi.org/10.1038/s41368-022-00209-w

 

  1. Shanthikumar S, Bekhit E, Bracken J, 2023, MRI as screening for pulmonary arteriovenous malformations in hereditary hemorrhagic telangiectasia. Pediatr Pulmonol, 58(4): 1281–1282. https://doi.org/10.1002/ppul.26297

 

  1. McDonald J, Bayrak-Toydemir P, Pyeritz RE, 2011, Hereditary hemorrhagic telangiectasia: An overview of diagnosis, management, and pathogenesis. Genet Med, 13(7): 607–616. https://doi.org/10.1097/GIM.0b013e3182136d32

 

  1. Vollherbst DF, Bendszus M, Mohlenbruch MA, 2020, Vascular malformations of the brain and its coverings. J Neuroendovascular Ther, 14(8): 285–294. https://doi.org/10.5797/jnet.ra.2020-0020
Conflict of interest
The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.
Share
Back to top
Gene & Protein in Disease, Electronic ISSN: 2811-003X Published by AccScience Publishing