{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T09:55:44Z","timestamp":1787738144068,"version":"build-2784847793"},"reference-count":110,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T00:00:00Z","timestamp":1764201600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["NIH\/NHLBI Catalyze R33 HL156141"],"award-info":[{"award-number":["NIH\/NHLBI Catalyze R33 HL156141"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Eloise & David Kimmelman Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Arteriovenous malformations (AVMs) are fast-flow vascular malformations formed by direct artery-to-vein shunts without an intervening capillary bed, which increases the risk of hemorrhage and organ-specific damage. A synthesis of recent advances shows that AVMs arise from interplay between germline susceptibility (ENG, ACVRL1, SMAD4, RASA1, EPHB4), somatic mosaicism (KRAS, MAP2K1, PIK3CA), perturbed signaling (TGF-\u03b2\/BMP, Notch, VEGF, PI3K\/AKT, RAS\/MAPK), hemodynamic stress, and inflammation. Multimodal imaging\u2014digital subtraction angiography (DSA), MRI\/MRA with perfusion and susceptibility sequences, CTA, Doppler ultrasound, and 3D rotational angiography\u2014underpins diagnosis and risk stratification, while arterial spin labeling and 4D flow techniques refine hemodynamic assessment. Management is individualized and multidisciplinary, combining endovascular embolization, microsurgical resection, and stereotactic radiosurgery (SRS); a non-surgical approach and monitoring remain reasonable for some asymptomatic AVMs. Device and technique innovations (detachable-tip microcatheters, pressure-cooker approaches, and newer liquid embolics such as PHIL and Squid) have broadened candidacy, and precision-medicine strategies, including pathway-targeted pharmacotherapy, are emerging for syndromic and somatic-mutation\u2013driven AVMs. Animal models and computational\/radiomics tools increasingly guide hypothesis generation and treatment selection. We outline practical updates and future priorities: integrated genomic-imaging risk scores, genotype-informed medical therapy, rational hybrid sequencing, and long-term outcome standards focused on hemorrhage prevention and quality of life.<\/jats:p>","DOI":"10.3390\/biom15121661","type":"journal-article","created":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T16:31:52Z","timestamp":1764261112000},"page":"1661","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Arteriovenous Malformations (AVMs): Molecular Pathogenesis, Clinical Features, and Emerging Therapeutic Strategies"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8142-6035","authenticated-orcid":false,"given":"Nga","family":"Le","sequence":"first","affiliation":[{"name":"DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA"},{"name":"Department of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Li","sequence":"additional","affiliation":[{"name":"DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7583-9042","authenticated-orcid":false,"given":"Gianni","family":"Walker","sequence":"additional","affiliation":[{"name":"DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bao-Ngoc","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Surgery, The George Washington University School of Medicine, Washington, DC 20037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2847-0613","authenticated-orcid":false,"given":"Arash","family":"Bornak","sequence":"additional","affiliation":[{"name":"DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sapna K.","family":"Deo","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omaida C.","family":"Velazquez","sequence":"additional","affiliation":[{"name":"DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA"},{"name":"Department of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA"},{"name":"Department of Radiology, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhao-Jun","family":"Liu","sequence":"additional","affiliation":[{"name":"DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA"},{"name":"Department of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"0312","DOI":"10.36922\/gpd.0312","article-title":"An updated review on the genetics of arteriovenous malformations","volume":"2","author":"Maddy","year":"2023","journal-title":"Gene Protein Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/B978-0-444-63640-9.00003-5","article-title":"Arteriovenous malformations: Epidemiology, clinical presentation, and diagnostic evaluation","volume":"143","author":"Osbun","year":"2017","journal-title":"Handb. Clin. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Schimmel, K., Ali, M.K., Tan, S.Y., Teng, J., Do, H.M., Steinberg, G.K., Stevenson, D.A., and Spiekerkoetter, E. (2021). Arteriovenous Malformations-Current Understanding of the Pathogenesis with Implications for Treatment. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22169037"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1161\/CIRCRESAHA.109.211037","article-title":"Pathogenesis of Arteriovenous Malformations in the Absence of Endoglin","volume":"106","author":"Mahmoud","year":"2010","journal-title":"Circ. Res."},{"key":"ref_5","first-page":"6","article-title":"Arteriovenous Malformation: Concepts on Physiopathology and Treatment","volume":"4","author":"Neto","year":"2019","journal-title":"J. Vasc. Endovasc. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1177\/159101990801400102","article-title":"Operative classification of brain arteriovenous malformations","volume":"14","author":"Beltramello","year":"2008","journal-title":"Interv. Neuroradiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.rvm.2015.06.001","article-title":"New classification of congenital vascular malformations (CVMs)","volume":"3","author":"Lee","year":"2015","journal-title":"Rev. Vasc. Med."},{"key":"ref_8","first-page":"e113","article-title":"Updated Classification of Vascular Anomalies: A living document from the International Society for the Study of Vascular Anomalies Classification Group","volume":"6","author":"Goldenberg","year":"2025","journal-title":"J. Vasc. Anom."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1111\/jop.13353","article-title":"Current classification of vascular anomalies of the head and neck","volume":"51","author":"Oomen","year":"2022","journal-title":"J. Oral Pathol. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1111\/cns.13200","article-title":"Risk factors for hemorrhage of brain arteriovenous malformation","volume":"25","author":"Shaligram","year":"2019","journal-title":"CNS Neurosci. Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1136\/jmg.2009.069013","article-title":"International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia","volume":"48","author":"Faughnan","year":"2011","journal-title":"J. Med. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1900","DOI":"10.1093\/brain\/124.10.1900","article-title":"A systematic review of the frequency and prognosis of arteriovenous malformations of the brain in adults","volume":"124","author":"Warlow","year":"2001","journal-title":"Brain"},{"key":"ref_13","doi-asserted-by":"crossref","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","year":"2014","journal-title":"Lancet"},{"key":"ref_14","unstructured":"Bokhari, M.R., and Bokhari, S.R.A. (2023, April 24). Arteriovenous Malformation of the Brain, StatPearls [Internet], Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK430744\/."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1007\/s00701-023-05612-8","article-title":"Recurrence of brain arteriovenous malformations in pediatric patients: A long-term follow-up study","volume":"165","author":"Oulasvirta","year":"2023","journal-title":"Acta Neurochir."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1007\/s10456-023-09881-w","article-title":"Localized conditional induction of brain arteriovenous malformations in a mouse model of hereditary hemorrhagic telangiectasia","volume":"26","author":"Scherschinski","year":"2023","journal-title":"Angiogenesis"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"633","DOI":"10.3171\/jns.2001.95.4.0633","article-title":"Population-based analysis of arteriovenous malformation treatment","volume":"95","author":"Hillman","year":"2001","journal-title":"J. Neurosurg."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"117ra8","DOI":"10.1126\/scitranslmed.3002670","article-title":"Notch4 normalization reduces blood vessel size in arteriovenous malformations","volume":"4","author":"Murphy","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1007\/s10456-018-9602-0","article-title":"Vascular deficiency of Smad4 causes arteriovenous malformations: A mouse model of Hereditary Hemorrhagic Telangiectasia","volume":"21","author":"Crist","year":"2018","journal-title":"Angiogenesis"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1007\/s10456-024-09953-5","article-title":"From bench to bedside: Murine models of inherited and sporadic brain arteriovenous malformations","volume":"28","author":"Ricciardelli","year":"2025","journal-title":"Angiogenesis"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1016\/j.jvs.2003.10.048","article-title":"Management of arteriovenous malformations: A multidisciplinary approach","volume":"39","author":"Lee","year":"2004","journal-title":"J. Vasc. Surg."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1159\/000346927","article-title":"Endovascular management of arteriovenous malformations of the brain","volume":"1","author":"Bruno","year":"2013","journal-title":"Interv. Neurol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"S90","DOI":"10.4103\/2152-7806.95420","article-title":"Embolization and radiosurgery for arteriovenous malformations","volume":"3","author":"Plasencia","year":"2012","journal-title":"Surg. Neurol. Int."},{"key":"ref_24","doi-asserted-by":"crossref","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","year":"2014","journal-title":"Angiogenesis"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1016\/j.ajhg.2019.09.010","article-title":"Somatic Mutations in Vascular Malformations of Hereditary Hemorrhagic Telangiectasia Result in Bi-allelic Loss of ENG or ACVRL1","volume":"105","author":"Snellings","year":"2019","journal-title":"Am. J. Hum. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"eabi7377","DOI":"10.1126\/science.abi7377","article-title":"A single-cell atlas of the normal and malformed human brain vasculature","volume":"375","author":"Winkler","year":"2022","journal-title":"Science"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1632","DOI":"10.1002\/humu.22431","article-title":"RASA1 mutations and associated phenotypes in 68 families with capillary malformation-arteriovenous malformation","volume":"34","author":"Revencu","year":"2013","journal-title":"Hum. Mutat."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3231","DOI":"10.1093\/brain\/awp246","article-title":"Notch-1 signalling is activated in brain arteriovenous malformations in humans","volume":"132","author":"ZhuGe","year":"2009","journal-title":"Brain"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1177\/0300060513478091","article-title":"Ephrin B2 and EphB4 selectively mark arterial and venous vessels in cerebral arteriovenous malformation","volume":"42","author":"Bai","year":"2014","journal-title":"J. Int. Med. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1038\/s12276-020-0414-0","article-title":"Dysregulation of the EphrinB2\u2212EphB4 ratio in pediatric cerebral arteriovenous malformations is associated with endothelial cell dysfunction in vitro and functions as a novel noninvasive biomarker in patients","volume":"52","author":"Fehnel","year":"2020","journal-title":"Exp. Mol. Med."},{"key":"ref_31","first-page":"187","article-title":"Doppler Sonography and 3D CT Angiography of Acquired Uterine Arteriovenous Malformations (AVMs): Report of Two Cases","volume":"8","author":"Aiyappan","year":"2014","journal-title":"J. Clin. Diagn. Res."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Irtyuga, O., Malashicheva, A., Zhiduleva, E., Freylikhman, O., Rotar, O., B\u00e4ck, M., Tarnovskaya, S., Kostareva, A., and Moiseeva, O. (2017). NOTCH1 Mutations in Aortic Stenosis: Association with Osteoprotegerin\/RANK\/RANKL. Biomed. Res. Int., 2017.","DOI":"10.1155\/2017\/6917907"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/j.yjmcc.2010.05.009","article-title":"Investigation of a transgenic mouse model of familial dilated cardiomyopathy","volume":"49","author":"Song","year":"2010","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s40348-021-00132-w","article-title":"Imaging of peripheral vascular malformations\u2014Current concepts and future perspectives","volume":"8","author":"Schmidt","year":"2021","journal-title":"Mol. Cell. Pediatr."},{"key":"ref_35","first-page":"Cd003436","article-title":"Interventions for treating brain arteriovenous malformations in adults","volume":"9","author":"Zuurbier","year":"2019","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1212\/WNL.0000000000010968","article-title":"Brain arteriovenous malformations: A review of natural history, pathobiology, and interventions","volume":"95","author":"Chen","year":"2020","journal-title":"Neurology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e172843","DOI":"10.1172\/JCI172843","article-title":"Shear stress and pathophysiological PI3K involvement in vascular malformations","volume":"134","author":"Ola","year":"2024","journal-title":"J. Clin. Investig."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Nakisli, S., Lagares, A., Nielsen, C.M., and Cuervo, H. (2023). Pericytes and vascular smooth muscle cells in central nervous system arteriovenous malformations. Front. Physiol., 14.","DOI":"10.3389\/fphys.2023.1210563"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Jeong, J.Y., Bafor, A., Freeman, B., Chen, P., Eun, S.P., and Kim, E. (2024). Pathophysiology in Brain Arteriovenous Malformations: Focus on Endothelial Dysfunctions and Endothelial-to-Mesenchymal Transition. Biomedicines, 12.","DOI":"10.3390\/biomedicines12081795"},{"key":"ref_40","first-page":"26","article-title":"High-output heart failure due to arteriovenous malformation treated by endovascular embolisation","volume":"29","author":"Liberman","year":"2022","journal-title":"Br. J. Cardiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"a006684","DOI":"10.1101\/cshperspect.a006684","article-title":"Vascular development in the zebrafish","volume":"2","author":"Gore","year":"2012","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1002\/dvg.20599","article-title":"Notch1 activation in mice causes arteriovenous malformations phenocopied by ephrinB2 and EphB4 mutants","volume":"48","author":"Krebs","year":"2010","journal-title":"Genesis"},{"key":"ref_43","first-page":"801","article-title":"The influence of hemodynamic and anatomic factors on hemorrhage from cerebral arteriovenous malformations","volume":"34","author":"Kader","year":"1994","journal-title":"Neurosurgery"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"335","DOI":"10.7461\/jcen.2014.16.4.335","article-title":"A comparative review of the hemodynamics and pathogenesis of cerebral and abdominal aortic aneurysms: Lessons to learn from each other","volume":"16","author":"Tanweer","year":"2014","journal-title":"J. Cerebrovasc. Endovasc. Neurosurg."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1186\/s13148-016-0248-8","article-title":"Genetic and epigenetic mechanisms in the development of arteriovenous malformations in the brain","volume":"8","author":"Thomas","year":"2016","journal-title":"Clin. Epigenet."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.3171\/foc.2001.11.5.2","article-title":"Epidemiology and natural history of arteriovenous malformations","volume":"11","author":"Stapf","year":"2001","journal-title":"Neurosurg. Focus"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2011","DOI":"10.1001\/jama.2011.1632","article-title":"Treatment of brain arteriovenous malformations: A systematic review and meta-analysis","volume":"306","author":"Buis","year":"2011","journal-title":"JAMA"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"437","DOI":"10.3171\/2012.10.JNS121280","article-title":"Natural history of cerebral arteriovenous malformations: A meta-analysis","volume":"118","author":"Gross","year":"2013","journal-title":"J. Neurosurg."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"15040","DOI":"10.1038\/hgv.2015.40","article-title":"Mutations in RASA1 and GDF2 identified in patients with clinical features of hereditary hemorrhagic telangiectasia","volume":"2","author":"Hernandez","year":"2015","journal-title":"Hum. Genome Var."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"McDonald, J., Wooderchak-Donahue, W., VanSant Webb, C., Whitehead, K., Stevenson, D.A., and Bayrak-Toydemir, P. (2015). Hereditary hemorrhagic telangiectasia: Genetics and molecular diagnostics in a new era. Front. Genet., 6.","DOI":"10.3389\/fgene.2015.00001"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.devcel.2011.01.011","article-title":"Endothelial Smad4 maintains cerebrovascular integrity by activating N-cadherin through cooperation with Notch","volume":"20","author":"Li","year":"2011","journal-title":"Dev. Cell"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1186\/s13148-022-01346-z","article-title":"DNA methylation signatures on vascular differentiation genes are aberrant in vessels of human cerebral arteriovenous malformation nidus","volume":"14","author":"Thomas","year":"2022","journal-title":"Clin. Epigenetics"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Drap\u00e9, E., Anquetil, T., Larriv\u00e9e, B., and Dubrac, A. (2022). Brain arteriovenous malformation in hereditary hemorrhagic telangiectasia: Recent advances in cellular and molecular mechanisms. Front. Hum. Neurosci., 16.","DOI":"10.3389\/fnhum.2022.1006115"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Xu, M., Xu, H., and Qin, Z. (2015). Animal Models in Studying Cerebral Arteriovenous Malformation. Biomed. Res. Int., 2015.","DOI":"10.1155\/2015\/178407"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1258\/shorts.2011.011057","article-title":"High output heart failure caused by a large pelvic arteriovenous malformation","volume":"2","author":"Koyalakonda","year":"2011","journal-title":"JRSM Short Rep."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Choi, E.J., Chen, W., Jun, K., Arthur, H.M., Young, W.L., and Su, H. (2014). Novel brain arteriovenous malformation mouse models for type 1 hereditary hemorrhagic telangiectasia. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0088511"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"861","DOI":"10.4070\/kcj.2012.42.12.861","article-title":"Two cases of high output heart failure caused by hereditary hemorrhagic telangiectasia","volume":"42","author":"Cho","year":"2012","journal-title":"Korean Circ. J."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"9884","DOI":"10.1073\/pnas.0504391102","article-title":"Endothelial expression of constitutively active Notch4 elicits reversible arteriovenous malformations in adult mice","volume":"102","author":"Carlson","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1161\/CIRCRESAHA.119.315974","article-title":"Loss of Endothelial Endoglin Promotes High-Output Heart Failure Through Peripheral Arteriovenous Shunting Driven by VEGF Signaling","volume":"126","author":"Redgrave","year":"2020","journal-title":"Circ. Res."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Jain, M.S., Do, H.M., and Massoud, T.F. (2019). Computational Network Modeling of Intranidal Hemodynamic Compartmentalization in a Theoretical Three-Dimensional Brain Arteriovenous Malformation. Front. Physiol., 10.","DOI":"10.3389\/fphys.2019.01250"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.3174\/ajnr.A3010","article-title":"Hemodynamic changes in patients with arteriovenous malformations assessed using high-resolution 3D radial phase-contrast MR angiography","volume":"33","author":"Chang","year":"2012","journal-title":"AJNR Am. J. Neuroradiol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1007\/s10439-012-0695-0","article-title":"High wall shear stress and spatial gradients in vascular pathology: A review","volume":"41","author":"Dolan","year":"2013","journal-title":"Ann. Biomed. Eng."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1227\/NEU.0000000000001300","article-title":"Molecular, Cellular, and Genetic Determinants of Sporadic Brain Arteriovenous Malformations","volume":"63","author":"Walcott","year":"2016","journal-title":"Neurosurgery"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1161\/STROKEAHA.115.002869","article-title":"Mouse Models of Cerebral Arteriovenous Malformation","volume":"47","author":"Nielsen","year":"2016","journal-title":"Stroke"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"e12554","DOI":"10.1111\/micc.12554","article-title":"The pericyte microenvironment during vascular development","volume":"26","author":"Payne","year":"2019","journal-title":"Microcirculation"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1007\/s00109-009-0463-2","article-title":"Regulation of vascular integrity","volume":"87","author":"Murakami","year":"2009","journal-title":"J. Mol. Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.hest.2020.10.005","article-title":"The role of mural cells in hemorrhage of brain arteriovenous malformation","volume":"2","author":"Pan","year":"2021","journal-title":"Brain Hemorrhages"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1007\/s00018-013-1475-1","article-title":"Endothelial signaling and the molecular basis of arteriovenous malformation","volume":"71","author":"Atri","year":"2014","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_69","first-page":"671","article-title":"Vascular smooth muscle cell differentiation in human cerebral vascular malformations","volume":"49","author":"Uranishi","year":"2001","journal-title":"Neurosurgery"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"115","DOI":"10.5999\/aps.2021.00626","article-title":"Wall shear stress on vascular smooth muscle cells exerts angiogenic effects on extracranial arteriovenous malformations","volume":"49","author":"Ryu","year":"2022","journal-title":"Arch. Plast. Surg."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"e3559","DOI":"10.1002\/jgm.3559","article-title":"Key biomarkers in cerebral arteriovenous malformations: Updated review","volume":"25","author":"Tanzadehpanah","year":"2023","journal-title":"J. Gene Med."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Scimone, C., Donato, L., Alafaci, C., Granata, F., Rinaldi, C., Longo, M., D\u2019Angelo, R., and Sidoti, A. (2020). High-Throughput Sequencing to Detect Novel Likely Gene-Disrupting Variants in Pathogenesis of Sporadic Brain Arteriovenous Malformations. Front. Genet., 11.","DOI":"10.3389\/fgene.2020.00146"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Liu, W., Morgan, K.M., and Pine, S.R. (2014). Activation of the Notch1 Stem Cell Signaling Pathway during Routine Cell Line Subculture. Front. Oncol., 4.","DOI":"10.3389\/fonc.2014.00211"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"669","DOI":"10.3892\/ijmm.2014.1818","article-title":"Constitutively active Notch1 signaling promotes endothelial-mesenchymal transition in a conditional transgenic mouse model","volume":"34","author":"Liu","year":"2014","journal-title":"Int. J. Mol. Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"5377","DOI":"10.1073\/pnas.101138098","article-title":"Notch signaling during vascular development","volume":"98","author":"Gridley","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/S0070-2153(10)92009-7","article-title":"Notch signaling in the vasculature","volume":"92","author":"Gridley","year":"2010","journal-title":"Curr. Top Dev. Biol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"33353","DOI":"10.18632\/oncotarget.16495","article-title":"Actin cytoskeleton regulator Arp2\/3 complex is required for DLL1 activating Notch1 signaling to maintain the stem cell phenotype of glioma initiating cells","volume":"8","author":"Zhang","year":"2017","journal-title":"Oncotarget"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1038\/s41392-022-00934-y","article-title":"Notch signaling pathway: Architecture, disease, and therapeutics","volume":"7","author":"Zhou","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1038\/nrm2009","article-title":"Notch signalling: A simple pathway becomes complex","volume":"7","author":"Bray","year":"2006","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_80","first-page":"6485","article-title":"Roles of notch signaling pathway and endothelial-mesenchymal transition in vascular endothelial dysfunction and atherosclerosis","volume":"22","author":"Lin","year":"2018","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_81","first-page":"675","article-title":"Notch-Tnf signalling is required for development and homeostasis of arterial valves","volume":"38","author":"Wang","year":"2017","journal-title":"Eur. Heart J."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1161\/CIRCRESAHA.107.167171","article-title":"Crosstalk Between Vascular Endothelial Growth Factor, Notch, and Transforming Growth Factor-\u03b2 in Vascular Morphogenesis","volume":"102","author":"Holderfield","year":"2008","journal-title":"Circ. Res."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Kopan, R. (2012). Notch signaling. Cold Spring Harb. Perspect. Biol., 4.","DOI":"10.1101\/cshperspect.a011213"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.atherosclerosis.2012.04.010","article-title":"Notch activation induces endothelial cell senescence and pro-inflammatory response: Implication of Notch signaling in atherosclerosis","volume":"225","author":"Liu","year":"2012","journal-title":"Atherosclerosis"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1002\/dvdy.24252","article-title":"The molecular regulation of arteriovenous specification and maintenance","volume":"244","author":"Fish","year":"2015","journal-title":"Dev. Dyn."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Russo, T.A., Banuth, A.M.M., Nader, H.B., and Dreyfuss, J.L. (2020). Altered shear stress on endothelial cells leads to remodeling of extracellular matrix and induction of angiogenesis. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0241040"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Wei, T., Richter, G.T., Zhang, H., Sun, R.W., Smith, C.H., and Strub, G.M. (2022). Extracranial arteriovenous malformations demonstrate dysregulated TGF-\u03b2\/BMP signaling and increased circulating TGF-\u03b21. Sci. Rep., 12.","DOI":"10.1038\/s41598-022-21217-0"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Munger, J.S., and Sheppard, D. (2011). Cross talk among TGF-\u03b2 signaling pathways, integrins, and the extracellular matrix. Cold Spring Harb. Perspect. Biol., 3.","DOI":"10.1101\/cshperspect.a005017"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Florian, I.A., Buruiana, A., Timis, T., Susman, S., Ioan, S.F., Balasa, A., and Berindan-Neagoe, I. (2021). Insight into the microRNAs Associated with Arteriovenous and Cavernous Malformations of the Brain. Cells, 10.","DOI":"10.3390\/cells10061373"},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Giotta Lucifero, A., and Luzzi, S. (2022). Brain AVMs-Related microRNAs: Machine Learning Algorithm for Expression Profiles of Target Genes. Brain Sci., 12.","DOI":"10.3390\/brainsci12121628"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"649036","DOI":"10.1155\/2014\/649036","article-title":"Cerebral arteriovenous malformations: Evaluation and management","volume":"2014","author":"Ajiboye","year":"2014","journal-title":"Sci. World J."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"76","DOI":"10.4103\/2152-7806.156866","article-title":"Diagnosis and evaluation of intracranial arteriovenous malformations","volume":"6","author":"Conger","year":"2015","journal-title":"Surg. Neurol. Int."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1161\/STROKEAHA.108.524678","article-title":"The natural history and predictive features of hemorrhage from brain arteriovenous malformations","volume":"40","author":"Wallace","year":"2009","journal-title":"Stroke"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"e182904","DOI":"10.1172\/JCI182904","article-title":"Epigenetics enters the stage in vascular malformations","volume":"134","year":"2024","journal-title":"J. Clin. Investig."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"H2250","DOI":"10.1152\/ajpheart.00083.2008","article-title":"Increased tissue perfusion promotes capillary dysplasia in the ALK1-deficient mouse brain following VEGF stimulation","volume":"295","author":"Hao","year":"2008","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_96","first-page":"030802","article-title":"Computational Fluid\u2013Structure Interactions in the Human Cerebrovascular System: Part 2\u2014A Review of Current Applications of Computational Fluid Dynamics and Structural Mechanics in Cerebrovascular Pathophysiology","volume":"5","author":"Achey","year":"2022","journal-title":"J. Eng. Sci. Med. Diagn. Ther."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1320","DOI":"10.2214\/AJR.16.17306","article-title":"Contemporary Imaging of Cerebral Arteriovenous Malformations","volume":"208","author":"Tranvinh","year":"2017","journal-title":"Am. J. Roentgenol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1152\/physiolgenomics.00005.2003","article-title":"Use of echocardiography for the phenotypic assessment of genetically altered mice","volume":"13","author":"Collins","year":"2003","journal-title":"Physiol. Genom."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1177\/1947601911423031","article-title":"Vascular Endothelial Growth Factor (VEGF) and Its Receptor (VEGFR) Signaling in Angiogenesis: A Crucial Target for Anti- and Pro-Angiogenic Therapies","volume":"2","author":"Shibuya","year":"2011","journal-title":"Genes Cancer"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"947","DOI":"10.3174\/ajnr.A1959","article-title":"Brain arteriovenous malformation treatment using a combination of Onyx and a new detachable tip microcatheter, SONIC: Short-term results","volume":"31","author":"Maimon","year":"2010","journal-title":"AJNR Am. J. Neuroradiol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"E7","DOI":"10.3171\/2017.2.FOCUS1755","article-title":"Novel use of flow diversion for the treatment of aneurysms associated with arteriovenous malformations","volume":"42","author":"Kilburg","year":"2017","journal-title":"Neurosurg. Focus"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1038\/nature09002","article-title":"Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis","volume":"465","author":"Wang","year":"2010","journal-title":"Nature"},{"key":"ref_103","first-page":"97","article-title":"Experimental Animal Models of Arteriovenous Malformation: A Review","volume":"2","author":"Raj","year":"2015","journal-title":"Vet. Sci."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1182\/blood.V93.1.184","article-title":"The Vascular Endothelial-Cadherin Promoter Directs Endothelial-Specific Expression in Transgenic Mice","volume":"93","author":"Gory","year":"1999","journal-title":"Blood"},{"key":"ref_105","doi-asserted-by":"crossref","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","year":"2012","journal-title":"Cerebrovasc. Dis."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/S0014-5793(02)02936-8","article-title":"Murine peripherin gene sequences direct Cre recombinase expression to peripheral neurons in transgenic mice","volume":"523","author":"Zhou","year":"2002","journal-title":"FEBS Lett."},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Ruiz, S., Zhao, H., Chandakkar, P., Prodyot, K.C., Papoin, J., Blanc, L., Metz, C., Campagne, F., and Marambaud, P. (2016). A mouse model of hereditary hemorrhagic telangiectasia generated by transmammary-delivered immunoblocking of BMP9 and BMP10. Sci. Rep., 6.","DOI":"10.1038\/srep37366"},{"key":"ref_108","first-page":"4055","article-title":"Lack of Flvcr2 impairs brain angiogenesis without affecting the blood-brain barrier","volume":"130","author":"Santander","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Davis, R.B., Pahl, K., Datto, N.C., Smith, S.V., Shawber, C., Caron, K.M., and Blatt, J. (2018). Notch signaling pathway is a potential therapeutic target for extracranial vascular malformations. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-36628-1"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.wneu.2020.06.118","article-title":"Embolic Agents and Microcatheters for Endovascular Treatment of Cerebral Arteriovenous Malformations","volume":"141","author":"Triano","year":"2020","journal-title":"World Neurosurg."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/12\/1661\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,29]],"date-time":"2025-11-29T05:11:24Z","timestamp":1764393084000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/12\/1661"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,27]]},"references-count":110,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["biom15121661"],"URL":"https:\/\/doi.org\/10.3390\/biom15121661","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,27]]}}}