{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T15:17:21Z","timestamp":1790176641387,"version":"4.1.0"},"reference-count":31,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,4,17]],"date-time":"2025-04-17T00:00:00Z","timestamp":1744848000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Erwin-R\u00f6ver-Stiftung","award":["BN"],"award-info":[{"award-number":["BN"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Brain arteriovenous malformations (bAVMs) are complex vascular lesions with significant clinical risks. The Hippo signaling pathway, particularly its downstream effector YAP, plays a crucial role in angiogenesis and vascular remodeling. This study investigates the role of YAP and related molecular markers in bAVMs, focusing on the effects of embolization. Immunohistochemical analysis was conducted on tissue samples from bAVM patients (n = 127), as well as on healthy blood vessels (n = 17). YAP, HIF-1\u03b1, FGFR1, CTGF, and CYR61 expression were quantified and correlated with clinical parameters. Results: In healthy vessels, YAP exhibited nuclear localization in (sub)endothelial cells and the tunica media, while CTGF and CYR61 were detected in the cytoplasm and extracellular matrix. The expression of YAP, CTGF, and CYR61 was significantly lower in bAVM tissues. Embolized bAVMs exhibited significantly higher expression of YAP, CTGF, and CYR61 compared to non-embolized tissues, suggesting a link between embolization and pro-angiogenic signaling. Additionally, FGFR1 was upregulated in embolized tissues. These results suggest that upregulation of YAP expression via the Hippo pathway might play a key role in bAVM pathophysiology. Embolization may further promote vascular remodeling. Dysregulation of YAP and related molecules in bAVMs warrants further studies to explore potential therapeutic strategies targeting the Hippo pathway.<\/jats:p>","DOI":"10.3390\/ijms26083791","type":"journal-article","created":{"date-parts":[[2025,4,17]],"date-time":"2025-04-17T04:16:21Z","timestamp":1744863381000},"page":"3791","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Role of Hippo Signaling in Brain Arteriovenous Malformations: Molecular Insights into Post-Embolization Remodeling"],"prefix":"10.3390","volume":"26","author":[{"given":"Belal","family":"Neyazi","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Otto-von-Guericke University, 39120 Magdeburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa Magdalena","family":"Swiatek","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Otto-von-Guericke University, 39120 Magdeburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7589-9984","authenticated-orcid":false,"given":"Mohammad Ali","family":"Karimpour","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Otto-von-Guericke University, 39120 Magdeburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Stassen","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Otto-von-Guericke University, 39120 Magdeburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus-Peter","family":"Stein","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Otto-von-Guericke University, 39120 Magdeburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Rashidi","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Otto-von-Guericke University, 39120 Magdeburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2075-9164","authenticated-orcid":false,"given":"Claudia Alexandra","family":"Dumitru","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Otto-von-Guericke University, 39120 Magdeburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5541-2411","authenticated-orcid":false,"given":"I. Erol","family":"Sandalcioglu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Otto-von-Guericke University, 39120 Magdeburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,17]]},"reference":[{"key":"ref_1","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_2","doi-asserted-by":"crossref","first-page":"1499","DOI":"10.1212\/WNL.0000000000004532","article-title":"Functional Impairments for Outcomes in a Randomized Trial of Unruptured Brain AVMs","volume":"89","author":"Mohr","year":"2017","journal-title":"Neurology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"15008","DOI":"10.1038\/nrdp.2015.8","article-title":"Brain Arteriovenous Malformations","volume":"1","author":"Lawton","year":"2015","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Boopathy, G.T.K., and Hong, W. (2019). Role of Hippo Pathway-YAP\/TAZ Signaling in Angiogenesis. Front. Cell Dev. Biol., 7.","DOI":"10.3389\/fcell.2019.00049"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/j.tcb.2015.05.002","article-title":"YAP and TAZ: A Nexus for Hippo Signaling and Beyond","volume":"25","author":"Hansen","year":"2015","journal-title":"Trends Cell Biol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Azad, T., Ghahremani, M., and Yang, X. (2019). The Role of YAP and TAZ in Angiogenesis and Vascular Mimicry. Cells, 8.","DOI":"10.3390\/cells8050407"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1038\/s41551-020-00657-x","article-title":"Matrix Stiffness Epigenetically Regulates the Oncogenic Activation of the Yes-Associated Protein in Gastric Cancer","volume":"5","author":"Jang","year":"2021","journal-title":"Nat. Biomed. Eng."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1038\/s41467-019-13771-5","article-title":"YAP1 Mediates Survival of ALK-Rearranged Lung Cancer Cells Treated with Alectinib via pro-Apoptotic Protein Regulation","volume":"11","author":"Tsuji","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/nature10137","article-title":"Role of YAP\/TAZ in Mechanotransduction","volume":"474","author":"Dupont","year":"2011","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1038\/nrm.2017.87","article-title":"Mechanobiology of YAP and TAZ in Physiology and Disease","volume":"18","author":"Panciera","year":"2017","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/s10020-021-00291-6","article-title":"Oscillatory Shear Stress Promotes Angiogenic Effects in Arteriovenous Malformations Endothelial Cells","volume":"27","author":"Ryu","year":"2021","journal-title":"Mol. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"11525","DOI":"10.1073\/pnas.1613121113","article-title":"Flow-Dependent YAP\/TAZ Activities Regulate Endothelial Phenotypes and Atherosclerosis","volume":"113","author":"Wang","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"15206","DOI":"10.1038\/ncomms15206","article-title":"YAP\/TAZ Link Cell Mechanics to Notch Signalling to Control Epidermal Stem Cell Fate","volume":"8","author":"Totaro","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1023\/A:1023823803510","article-title":"Regulation of Angiogenesis and Endothelial Cell Function by Connective Tissue Growth Factor (CTGF) and Cysteine-Rich 61 (CYR61)","volume":"5","author":"Brigstock","year":"2002","journal-title":"Angiogenesis"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.vph.2013.01.004","article-title":"Connective Tissue Growth Factor (CCN2) in Blood Vessels","volume":"58","author":"Ponticos","year":"2013","journal-title":"Vasc. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1962","DOI":"10.1101\/gad.1664408","article-title":"TEAD Mediates YAP-Dependent Gene Induction and Growth Control","volume":"22","author":"Zhao","year":"2008","journal-title":"Genes. Dev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1038\/s41392-022-01191-9","article-title":"The Hippo Signalling Pathway and Its Implications in Human Health and Diseases","volume":"7","author":"Fu","year":"2022","journal-title":"Sig Transduct. Target. Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1101\/gad.173435.111","article-title":"Cell Detachment Activates the Hippo Pathway via Cytoskeleton Reorganization to Induce Anoikis","volume":"26","author":"Zhao","year":"2012","journal-title":"Genes. Dev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1159\/000090526","article-title":"Vascular Endothelial Growth Factor Plasma Levels Are Significantly Elevated in Patients with Cerebral Arteriovenous Malformations","volume":"21","author":"Sandalcioglu","year":"2006","journal-title":"Cerebrovasc. Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1159\/000319568","article-title":"Proliferation Activity Is Significantly Elevated in Partially Embolized Cerebral Arteriovenous Malformations","volume":"30","author":"Sandalcioglu","year":"2010","journal-title":"Cerebrovasc. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1016\/j.apsb.2019.12.010","article-title":"Yes-Associated Protein (YAP) and Transcriptional Coactivator with a PDZ-Binding Motif (TAZ): A Nexus between Hypoxia and Cancer","volume":"10","author":"Zhao","year":"2020","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"8031","DOI":"10.1074\/jbc.M115.698472","article-title":"A Hippo and Fibroblast Growth Factor Receptor Autocrine Pathway in Cholangiocarcinoma","volume":"291","author":"Ilyas","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1161\/CIRCULATIONAHA.120.053047","article-title":"Defective Flow-Migration Coupling Causes Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia","volume":"144","author":"Park","year":"2021","journal-title":"Circulation"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5942379","DOI":"10.1155\/2022\/5942379","article-title":"YAP Overexpression in Breast Cancer Cells Promotes Angiogenesis through Activating YAP Signaling in Vascular Endothelial Cells","volume":"2022","author":"Yan","year":"2022","journal-title":"Anal. Cell. Pathol."},{"key":"ref_25","first-page":"10","article-title":"Human Brain Arteriovenous Malformations Are Associated with Interruptions in Elastic Fibers and Changes in Collagen Content","volume":"23","author":"Guo","year":"2012","journal-title":"Turk. Neurosurg."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"105589","DOI":"10.1016\/j.clineuro.2019.105589","article-title":"Age-Dependent Changes of Collagen Alpha-2(IV) Expression in the Extracellular Matrix of Brain Arteriovenous Malformations","volume":"189","author":"Neyazi","year":"2020","journal-title":"Clin. Neurol. Neurosurg."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e14136","DOI":"10.1111\/cns.14136","article-title":"Vascular Stability of Brain Arteriovenous Malformations after Partial Embolization","volume":"30","author":"He","year":"2024","journal-title":"CNS Neurosci. Ther."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"11233","DOI":"10.1073\/pnas.1913716117","article-title":"Nonlinear Hydrodynamic Instability and Turbulence in Pulsatile Flow","volume":"117","author":"Xu","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1016\/j.devcel.2017.02.019","article-title":"Flow-Dependent Endothelial YAP Regulation Contributes to Vessel Maintenance","volume":"40","author":"Nakajima","year":"2017","journal-title":"Dev. Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.canlet.2018.02.015","article-title":"The Hippo\/YAP1 Pathway Interacts with FGFR1 Signaling to Maintain Stemness in Lung Cancer","volume":"423","author":"Lu","year":"2018","journal-title":"Cancer Lett."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4232","DOI":"10.1210\/en.2011-0234","article-title":"Effect of CCN2 on FGF2-Induced Proliferation and MMP9 and MMP13 Productions by Chondrocytes","volume":"152","author":"Nishida","year":"2011","journal-title":"Endocrinology"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/8\/3791\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:16:09Z","timestamp":1760030169000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/8\/3791"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,17]]},"references-count":31,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["ijms26083791"],"URL":"https:\/\/doi.org\/10.3390\/ijms26083791","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,17]]}}}