{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T01:46:54Z","timestamp":1782870414764,"version":"3.54.5"},"reference-count":61,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T00:00:00Z","timestamp":1778198400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":54,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["24POST1191892"],"award-info":[{"award-number":["24POST1191892"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014440","name":"Ministerio de Ciencia, Innovaci\u00f3n y Universidades","doi-asserted-by":"publisher","award":["PID2021-123365OB-I00"],"award-info":[{"award-number":["PID2021-123365OB-I00"]}],"id":[{"id":"10.13039\/100014440","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ministerio de Ciencia, Innovaci\u00f3n y Universidades,Spain","award":["SFB958"],"award-info":[{"award-number":["SFB958"]}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SE2016\/10-1"],"award-info":[{"award-number":["SE2016\/10-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001674","name":"Fondation Leducq","doi-asserted-by":"publisher","award":["21CVD03 - ReVAMP"],"award-info":[{"award-number":["21CVD03 - ReVAMP"]}],"id":[{"id":"10.13039\/501100001674","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1HL141131"],"award-info":[{"award-number":["1HL141131"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100031366","name":"ERA-Net NEURON","doi-asserted-by":"publisher","award":["01EW2306"],"award-info":[{"award-number":["01EW2306"]}],"id":[{"id":"10.13039\/100031366","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Med"],"DOI":"10.1186\/s10020-026-01495-4","type":"journal-article","created":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T01:44:38Z","timestamp":1778204678000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of the adhesion GPCR ADGRL4\/ELTD1 as a novel potential prognostic biomarker for cerebral cavernous malformation disease"],"prefix":"10.1186","volume":"32","author":[{"given":"Andrea","family":"Perrelli","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashraqat","family":"Ahmed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Onisiforou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gwenola","family":"Boulday","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Zalvide","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celia M.","family":"Pombo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 E.","family":"Mart\u00ednez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessio","family":"Paolini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salim","family":"Abdelilah-Seyfried","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioannis","family":"Petrakakis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfram S.","family":"Kunz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Geffers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Hartmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter","family":"Bini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerasimos","family":"Baltsavias","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amir","family":"Samii","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helmut","family":"Bertalanffy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saverio F.","family":"Retta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela J.","family":"Glading","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Souvik","family":"Kar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,8]]},"reference":[{"key":"1495_CR1","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1016\/j.freeradbiomed.2017.11.014","volume":"115","author":"C Antognelli","year":"2018","unstructured":"Antognelli C, Trapani E, Delle Monache S, Perrelli A, Daga M, Pizzimenti S, et al. KRIT1 loss-of-function induces a chronic Nrf2-mediated adaptive homeostasis that sensitizes cells to oxidative stress: implication for Cerebral Cavernous Malformation disease. Free Radic Biol Med. 2018;115:202\u201318.","journal-title":"Free Radic Biol Med"},{"issue":"5-6","key":"1495_CR2","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1159\/000463392","volume":"43","author":"A Arauz","year":"2017","unstructured":"Arauz A, Pati\u00f1o-Rodriguez HM, Chavarria-Medina M, Becerril M, Longo GM, Nathal E. Rebleeding and outcome in patients with symptomatic brain stem cavernomas. Cerebrovasc Dis. 2017;43(5\u20136):283\u20139.","journal-title":"Cerebrovasc Dis"},{"key":"1495_CR3","doi-asserted-by":"crossref","unstructured":"Assmann JC, M\u00fcller K, Wenzel J, Walther T, Brands J, Thornton P, et al. Isolation and Cultivation of Primary Brain Endothelial Cells from Adult Mice. Bio Protoc. 2017;7(10):e2294.","DOI":"10.21769\/BioProtoc.2294"},{"issue":"1","key":"1495_CR4","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1111\/j.1399-0004.2012.01892.x","volume":"83","author":"S Bacigaluppi","year":"2013","unstructured":"Bacigaluppi S, Retta SF, Pileggi S, Fontanella M, Goitre L, Tassi L, et al. Genetic and cellular basis of cerebral cavernous malformations: implications for clinical management. Clin Genet. 2013;83(1):7\u201314.","journal-title":"Clin Genet"},{"key":"1495_CR5","doi-asserted-by":"publisher","DOI":"10.3389\/fsurg.2016.00060","volume":"3","author":"JF Baranoski","year":"2016","unstructured":"Baranoski JF, Kalani MY, Przybylowski CJ, Zabramski JM. Cerebral cavernous malformations: review of the genetic and protein-protein interactions resulting in disease pathogenesis. Front Surg. 2016;3:60.","journal-title":"Front Surg"},{"issue":"1\u20132","key":"1495_CR6","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s101430100179","volume":"25","author":"H Bertalanffy","year":"2002","unstructured":"Bertalanffy H, Benes L, Miyazawa T, Alberti O, Siegel AM, Sure U. Cerebral cavernomas in the adult. Review of the literature and analysis of 72 surgically treated patients. Neurosurg Rev. 2002;25(1\u20132):1\u201353.","journal-title":"Neurosurg Rev"},{"issue":"3\u20134","key":"1495_CR7","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1242\/dmm.001263","volume":"2","author":"G Boulday","year":"2009","unstructured":"Boulday G, Bl\u00e9con A, Petit N, Chareyre F, Garcia LA, Niwa-Kawakita M, et al. Tissue-specific conditional CCM2 knockout mice establish the essential role of endothelial CCM2 in angiogenesis: implications for human cerebral cavernous malformations. Dis Model Mech. 2009;2(3\u20134):168\u201377.","journal-title":"Dis Model Mech"},{"issue":"27","key":"1495_CR8","doi-asserted-by":"publisher","first-page":"8421","DOI":"10.1073\/pnas.1501352112","volume":"112","author":"L Bravi","year":"2015","unstructured":"Bravi L, Rudini N, Cuttano R, Giampietro C, Maddaluno L, Ferrarini L, et al. Sulindac metabolites decrease cerebrovascular malformations in CCM3-knockout mice. Proc Natl Acad Sci U S A. 2015;112(27):8421\u20136.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"4","key":"1495_CR9","first-page":"495","volume":"49","author":"I Buzatu","year":"2023","unstructured":"Buzatu I, Tache DE, Manea Carneluti EV, Zlatian O. ELTD1 review: new regulator of angiogenesis in glioma. Curr Health Sci J. 2023;49(4):495\u2013502.","journal-title":"Curr Health Sci J"},{"issue":"3","key":"1495_CR10","first-page":"211","volume":"59","author":"H Choquet","year":"2015","unstructured":"Choquet H, Pawlikowska L, Lawton MT, Kim H. Genetics of cerebral cavernous malformations: current status and future prospects. J Neurosurg Sci. 2015;59(3):211\u201320.","journal-title":"J Neurosurg Sci"},{"key":"1495_CR11","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1016\/j.freeradbiomed.2016.01.008","volume":"92","author":"H Choquet","year":"2016","unstructured":"Choquet H, Trapani E, Goitre L, Trabalzini L, Akers A, Fontanella M, et al. Cytochrome P450 and matrix metalloproteinase genetic modifiers of disease severity in cerebral cavernous malformation type 1. Free Radic Biol Med. 2016;92:100\u20139.","journal-title":"Free Radic Biol Med"},{"key":"1495_CR12","doi-asserted-by":"publisher","DOI":"10.3390\/antiox8010027","author":"L Cianfruglia","year":"2019","unstructured":"Cianfruglia L, Perrelli A, Fornelli C, Magini A, Gorbi S, Salzano AM, et al. KRIT1 loss-of-function associated with Cerebral Cavernous Malformation Disease leads to enhanced S-Glutathionylation of distinct structural and regulatory proteins. Antioxidants Basel. 2019;8(1):27. https:\/\/doi.org\/10.3390\/antiox8010027.","journal-title":"Antioxidants Basel"},{"issue":"46","key":"1495_CR13","doi-asserted-by":"publisher","first-page":"14284","DOI":"10.1073\/pnas.1510495112","volume":"112","author":"X Cullere","year":"2015","unstructured":"Cullere X, Plovie E, Bennett PM, MacRae CA, Mayadas TN. The cerebral cavernous malformation proteins CCM2L and CCM2 prevent the activation of the MAP kinase MEKK3. Proc Natl Acad Sci U S A. 2015;112(46):14284\u20139.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"1495_CR14","doi-asserted-by":"crossref","unstructured":"Czupalla CJ, Yousef H, Wyss-Coray T, Butcher EC. Collagenase-based Single Cell Isolation of Primary Murine Brain Endothelial Cells Using Flow Cytometry. Bio Protoc. 2018;8(22):e3092.","DOI":"10.21769\/BioProtoc.3092"},{"issue":"2","key":"1495_CR15","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1016\/j.bbrc.2015.10.006","volume":"467","author":"S Dai","year":"2015","unstructured":"Dai S, Wang X, Li X, Cao Y. MicroRNA-139-5p acts as a tumor suppressor by targeting ELTD1 and regulating cell cycle in glioblastoma multiforme. Biochem Biophys Res Commun. 2015;467(2):204\u201310.","journal-title":"Biochem Biophys Res Commun"},{"issue":"1","key":"1495_CR16","doi-asserted-by":"publisher","first-page":"632","DOI":"10.1111\/jcmm.14773","volume":"24","author":"PV DiStefano","year":"2020","unstructured":"DiStefano PV, Glading AJ. VEGF signalling enhances lesion burden in KRIT1 deficient mice. J Cell Mol Med. 2020;24(1):632\u20139.","journal-title":"J Cell Mol Med"},{"issue":"47","key":"1495_CR17","doi-asserted-by":"publisher","first-page":"33054","DOI":"10.1074\/jbc.M114.582304","volume":"289","author":"PV DiStefano","year":"2014","unstructured":"DiStefano PV, Kuebel JM, Sarelius IH, Glading AJ. KRIT1 protein depletion modifies endothelial cell behavior via increased vascular endothelial growth factor (VEGF) signaling. J Biol Chem. 2014;289(47):33054\u201365.","journal-title":"J Biol Chem"},{"issue":"Pt 4","key":"1495_CR18","first-page":"701","volume":"127","author":"KM Draheim","year":"2014","unstructured":"Draheim KM, Fisher OS, Boggon TJ, Calderwood DA. Cerebral cavernous malformation proteins at a glance. J Cell Sci. 2014;127(Pt 4):701\u20137.","journal-title":"J Cell Sci"},{"issue":"1","key":"1495_CR19","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1186\/s12862-019-1445-9","volume":"19","author":"DM Favara","year":"2019","unstructured":"Favara DM, Banham AH, Harris AL. ADGRL4\/ELTD1 is a highly conserved angiogenesis-associated orphan adhesion GPCR that emerged with the first vertebrates and comprises 3 evolutionary variants. BMC Evol Biol. 2019;19(1):143.","journal-title":"BMC Evol Biol"},{"key":"1495_CR20","doi-asserted-by":"publisher","DOI":"10.3390\/metabo9120287","author":"DM Favara","year":"2019","unstructured":"Favara DM, Zois CE, Haider S, Pires E, Sheldon H, McCullagh J, et al. ADGRL4\/ELTD1 silencing in endothelial cells induces ACLY and SLC25A1 and alters the cellular metabolic profile. Metabolites. 2019. https:\/\/doi.org\/10.3390\/metabo9120287.","journal-title":"Metabolites"},{"issue":"1","key":"1495_CR21","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-85408-x","volume":"11","author":"DM Favara","year":"2021","unstructured":"Favara DM, Liebscher I, Jazayeri A, Nambiar M, Sheldon H, Banham AH, et al. Elevated expression of the adhesion GPCR ADGRL4\/ELTD1 promotes endothelial sprouting angiogenesis without activating canonical GPCR signalling. Sci Rep. 2021;11(1):8870.","journal-title":"Sci Rep"},{"key":"1495_CR22","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2020.109527","volume":"68","author":"F Finetti","year":"2020","unstructured":"Finetti F, Schiavo I, Ercoli J, Zotta A, Boda E, Retta SF, et al. KRIT1 loss-mediated upregulation of NOX1 in stromal cells promotes paracrine pro-angiogenic responses. Cell Signal. 2020;68:109527.","journal-title":"Cell Signal"},{"key":"1495_CR23","doi-asserted-by":"crossref","unstructured":"Fusco C, Nardella G, Di Filippo L, Dejana E, Cacchiarelli D, Petracca A, et al. Transcriptome Analysis Reveals Altered Expression of Genes Involved in Hypoxia, Inflammation and Immune Regulation in Pdcd10-Depleted Mouse Endothelial Cells. Genes (Basel). 2022;13(6):961.","DOI":"10.3390\/genes13060961"},{"issue":"7","key":"1495_CR24","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0011786","volume":"5","author":"L Goitre","year":"2010","unstructured":"Goitre L, Balzac F, Degani S, Degan P, Marchi S, Pinton P, et al. KRIT1 regulates the homeostasis of intracellular reactive oxygen species. PLoS One. 2010;5(7):e11786.","journal-title":"PLoS One"},{"key":"1495_CR25","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1016\/j.freeradbiomed.2013.11.020","volume":"68","author":"L Goitre","year":"2014","unstructured":"Goitre L, De Luca E, Braggion S, Trapani E, Guglielmotto M, Biasi F, et al. KRIT1 loss of function causes a ROS-dependent upregulation of c-Jun. Free Radic Biol Med. 2014;68:134\u201347.","journal-title":"Free Radic Biol Med"},{"issue":"1","key":"1495_CR26","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-08373-4","volume":"7","author":"L Goitre","year":"2017","unstructured":"Goitre L, DiStefano PV, Moglia A, Nobiletti N, Baldini E, Trabalzini L, et al. Up-regulation of NADPH oxidase-mediated redox signaling contributes to the loss of barrier function in KRIT1 deficient endothelium. Sci Rep. 2017;7(1):8296.","journal-title":"Sci Rep"},{"issue":"6","key":"1495_CR27","doi-asserted-by":"publisher","first-page":"1153","DOI":"10.1177\/0271678X251314366","volume":"45","author":"SF Hage","year":"2025","unstructured":"Hage SF, Bi DE, Kinkade S, Vera Cruz D, Srinath A, Jhaveri A, et al. Circulating molecules reflect imaging biomarkers of hemorrhage in cerebral cavernous malformations. J Cereb Blood Flow Metab. 2025;45(6):1153\u201365.","journal-title":"J Cereb Blood Flow Metab"},{"issue":"3","key":"1495_CR28","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1093\/neuonc\/noab181","volume":"24","author":"H Huang","year":"2022","unstructured":"Huang H, Georganaki M, Conze LL, Lavi\u00f1a B, van Hooren L, Vemuri K, et al. ELTD1 deletion reduces vascular abnormality and improves T-cell recruitment after PD-1 blockade in glioma. Neuro Oncol. 2022;24(3):398\u2013411.","journal-title":"Neuro Oncol"},{"issue":"4","key":"1495_CR29","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1007\/s10143-015-0699-y","volume":"39","author":"S Kar","year":"2016","unstructured":"Kar S, Baisantry A, Nabavi A, Bertalanffy H. Role of Delta-Notch signaling in cerebral cavernous malformations. Neurosurg Rev. 2016;39(4):581\u20139.","journal-title":"Neurosurg Rev"},{"issue":"2","key":"1495_CR30","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1007\/s12031-017-0880-6","volume":"61","author":"S Kar","year":"2017","unstructured":"Kar S, Bali KK, Baisantry A, Geffers R, Samii A, Bertalanffy H. Genome-wide sequencing reveals microRNAs downregulated in cerebral cavernous malformations. J Mol Neurosci. 2017;61(2):178\u201388.","journal-title":"J Mol Neurosci"},{"issue":"1","key":"1495_CR31","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-50375-x","volume":"9","author":"J Li","year":"2019","unstructured":"Li J, Shen J, Wang Z, Xu H, Wang Q, Chai S, et al. ELTD1 facilitates glioma proliferation, migration and invasion by activating JAK\/STAT3\/HIF-1\u03b1 signaling axis. Sci Rep. 2019;9(1):13904.","journal-title":"Sci Rep"},{"issue":"4","key":"1495_CR32","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1006\/meth.2001.1262","volume":"25","author":"KJ Livak","year":"2001","unstructured":"Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 2001;25(4):402\u20138.","journal-title":"Methods"},{"issue":"11","key":"1495_CR33","doi-asserted-by":"publisher","first-page":"3331","DOI":"10.1084\/jem.20171178","volume":"214","author":"MA Lopez-Ramirez","year":"2017","unstructured":"Lopez-Ramirez MA, Fonseca G, Zeineddine HA, Girard R, Moore T, Pham A, et al. Thrombospondin1 (TSP1) replacement prevents cerebral cavernous malformations. J Exp Med. 2017;214(11):3331\u201346.","journal-title":"J Exp Med"},{"issue":"12","key":"1495_CR34","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8","volume":"15","author":"MI Love","year":"2014","unstructured":"Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15(12):550.","journal-title":"Genome Biol"},{"issue":"8","key":"1495_CR35","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0183166","volume":"12","author":"S Lu","year":"2017","unstructured":"Lu S, Liu S, Wietelmann A, Kojonazarov B, Atzberger A, Tang C, et al. Developmental vascular remodeling defects and postnatal kidney failure in mice lacking Gpr116 (Adgrf5) and Eltd1 (Adgrl4). PLoS One. 2017;12(8):e0183166.","journal-title":"PLoS One"},{"issue":"2","key":"1495_CR36","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1016\/j.ccr.2013.06.004","volume":"24","author":"M Masiero","year":"2013","unstructured":"Masiero M, Sim\u00f5es FC, Han HD, Snell C, Peterkin T, Bridges E, et al. A core human primary tumor angiogenesis signature identifies the endothelial orphan receptor ELTD1 as a key regulator of angiogenesis. Cancer Cell. 2013;24(2):229\u201341.","journal-title":"Cancer Cell"},{"issue":"6","key":"1495_CR37","doi-asserted-by":"publisher","first-page":"4150","DOI":"10.1074\/jbc.M004814200","volume":"276","author":"T Nechiporuk","year":"2001","unstructured":"Nechiporuk T, Urness LD, Keating MT. ETL, a novel seven-transmembrane receptor that is developmentally regulated in the heart. ETL is a member of the secretin family and belongs to the epidermal growth factor-seven-transmembrane subfamily. J Biol Chem. 2001;276(6):4150\u20137.","journal-title":"J Biol Chem"},{"key":"1495_CR38","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.61413","volume":"9","author":"F Orsenigo","year":"2020","unstructured":"Orsenigo F, Conze LL, Jauhiainen S, Corada M, Lazzaroni F, Malinverno M, et al. Mapping endothelial-cell diversity in cerebral cavernous malformations at single-cell resolution. Elife. 2020;9:9.","journal-title":"Elife"},{"key":"1495_CR39","doi-asserted-by":"crossref","unstructured":"Perrelli A, Ferraris C, Berni E, Glading AJ, Retta SF. KRIT1: A Traffic Warden at the Busy Crossroads Between Redox Signaling and the Pathogenesis of Cerebral Cavernous Malformation Disease. Antioxid Redox Signal. 2023;38(7-9):496\u2013528.","DOI":"10.1089\/ars.2021.0263"},{"key":"1495_CR40","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1016\/j.freeradbiomed.2021.06.021","volume":"172","author":"A Perrelli","year":"2021","unstructured":"Perrelli A, Retta SF. Polymorphisms in genes related to oxidative stress and inflammation: emerging links with the pathogenesis and severity of cerebral cavernous malformation disease. Free Radic Biol Med. 2021;172:403\u201317.","journal-title":"Free Radic Biol Med"},{"issue":"9","key":"1495_CR41","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/29.9.e45","volume":"29","author":"MW Pfaffl","year":"2001","unstructured":"Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 2001;29(9):e45.","journal-title":"Nucleic Acids Res"},{"issue":"7862","key":"1495_CR42","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1038\/s41586-021-03562-8","volume":"594","author":"AA Ren","year":"2021","unstructured":"Ren AA, Snellings DA, Su YS, Hong CC, Castro M, Tang AT, et al. PIK3CA and CCM mutations fuel cavernomas through a cancer-like mechanism. Nature. 2021;594(7862):271\u20136.","journal-title":"Nature"},{"issue":"2","key":"1495_CR43","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1016\/j.devcel.2014.12.016","volume":"32","author":"M Renz","year":"2015","unstructured":"Renz M, Otten C, Faurobert E, Rudolph F, Zhu Y, Boulday G, et al. Regulation of beta1 integrin-Klf2-mediated angiogenesis by CCM proteins. Dev Cell. 2015;32(2):181\u201390.","journal-title":"Dev Cell"},{"issue":"5","key":"1495_CR44","doi-asserted-by":"publisher","first-page":"1337","DOI":"10.1161\/STROKEAHA.114.007512","volume":"46","author":"GB Schulz","year":"2015","unstructured":"Schulz GB, Wieland E, W\u00fcstehube-Lausch J, Boulday G, Moll I, Tournier-Lasserve E, et al. Cerebral Cavernous Malformation-1 protein controls DLL4-Notch3 signaling between the endothelium and pericytes. Stroke. 2015;46(5):1337\u201343.","journal-title":"Stroke"},{"key":"1495_CR45","first-page":"3767","volume":"8","author":"F Serban","year":"2015","unstructured":"Serban F, Artene SA, Georgescu AM, Purcaru SO, Tache DE, Alexandru O, et al. Epidermal growth factor, latrophilin, and seven transmembrane domain-containing protein 1 marker, a novel angiogenesis marker. Onco Targets Ther. 2015;8:3767\u201374.","journal-title":"Onco Targets Ther"},{"issue":"1","key":"1495_CR46","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1080\/15321819.2016.1209217","volume":"38","author":"F Serban","year":"2017","unstructured":"Serban F, Daianu O, Tataranu LG, Artene SA, Emami G, Georgescu AM, et al. Silencing of epidermal growth factor, latrophilin and seven transmembrane domain-containing protein 1 (ELTD1) via siRNA-induced cell death in glioblastoma. J Immunoassay Immunochem. 2017;38(1):21\u201333.","journal-title":"J Immunoassay Immunochem"},{"issue":"11","key":"1495_CR47","doi-asserted-by":"publisher","first-page":"1957","DOI":"10.1158\/1541-7786.MCR-21-0171","volume":"19","author":"H Sheldon","year":"2021","unstructured":"Sheldon H, Bridges E, Silva I, Masiero M, Favara DM, Wang D, et al. ADGRL4\/ELTD1 expression in breast cancer cells induces vascular normalization and immune suppression. Mol Cancer Res. 2021;19(11):1957\u201369.","journal-title":"Mol Cancer Res"},{"issue":"8","key":"1495_CR48","doi-asserted-by":"publisher","DOI":"10.1002\/jex2.52","volume":"1","author":"H Sheldon","year":"2022","unstructured":"Sheldon H, Zhang W, Bridges E, Ang KH, Lin S, Masiero M, et al. ELTD1 is present in extracellular vesicles derived from endothelial cells as a cleaved extracellular domain which induces in vivo angiogenesis. J Extracell Biol. 2022;1(8):e52.","journal-title":"J Extracell Biol"},{"issue":"1","key":"1495_CR49","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-54845-0","volume":"9","author":"S Subhash","year":"2019","unstructured":"Subhash S, Kalmbach N, Wegner F, Petri S, Glomb T, Dittrich-Breiholz O, et al. Transcriptome-wide profiling of cerebral cavernous malformations patients reveal important long noncoding RNA molecular signatures. Sci Rep. 2019;9(1):18203.","journal-title":"Sci Rep"},{"key":"1495_CR50","doi-asserted-by":"publisher","first-page":"4897","DOI":"10.2147\/IJGM.S325495","volume":"14","author":"B Sun","year":"2021","unstructured":"Sun B, Zhong FJ. ELTD1 promotes gastric cancer cell proliferation, invasion and epithelial-mesenchymal transition through MAPK\/ERK signaling by regulating CSK. Int J Gen Med. 2021;14:4897\u2013911.","journal-title":"Int J Gen Med"},{"issue":"12","key":"1495_CR51","doi-asserted-by":"publisher","first-page":"3048","DOI":"10.7150\/ijbs.62293","volume":"17","author":"J Sun","year":"2021","unstructured":"Sun J, Zhang Z, Chen J, Xue M, Pan X. ELTD1 promotes invasion and metastasis by activating MMP2 in colorectal cancer. Int J Biol Sci. 2021;17(12):3048\u201358.","journal-title":"Int J Biol Sci"},{"key":"1495_CR52","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaw3521","author":"AT Tang","year":"2019","unstructured":"Tang AT, Sullivan KR, Hong CC, Goddard LM, Mahadevan A, Ren A, et al. Distinct cellular roles for PDCD10 define a gut-brain axis in cerebral cavernous malformation. Sci Transl Med. 2019. https:\/\/doi.org\/10.1126\/scitranslmed.aaw3521.","journal-title":"Sci Transl Med"},{"issue":"1","key":"1495_CR53","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1227\/NEU.0b013e318276b29d","volume":"72","author":"RA Towner","year":"2013","unstructured":"Towner RA, Jensen RL, Colman H, Vaillant B, Smith N, Casteel R, et al. ELTD1, a potential new biomarker for gliomas. Neurosurgery. 2013;72(1):77\u201390.","journal-title":"Neurosurgery"},{"issue":"3","key":"1495_CR54","first-page":"201","volume":"59","author":"E Trapani","year":"2015","unstructured":"Trapani E, Retta SF. Cerebral cavernous malformation (CCM) disease: from monogenic forms to genetic susceptibility factors. J Neurosurg Sci. 2015;59(3):201\u20139.","journal-title":"J Neurosurg Sci"},{"issue":"4","key":"1495_CR55","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1038\/jcbfm.2014.27","volume":"34","author":"BP Walcott","year":"2014","unstructured":"Walcott BP, Peterson RT. Zebrafish models of cerebrovascular disease. J Cereb Blood Flow Metab. 2014;34(4):571\u20137.","journal-title":"J Cereb Blood Flow Metab"},{"issue":"28","key":"1495_CR56","doi-asserted-by":"publisher","first-page":"12640","DOI":"10.1073\/pnas.1000132107","volume":"107","author":"J Wustehube","year":"2010","unstructured":"Wustehube J, Bartol A, Liebler SS, Brutsch R, Zhu Y, Felbor U, et al. Cerebral cavernous malformation protein CCM1 inhibits sprouting angiogenesis by activating DELTA-NOTCH signaling. Proc Natl Acad Sci U S A. 2010;107(28):12640\u20135.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"5","key":"1495_CR57","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0035779","volume":"7","author":"J Xiao","year":"2012","unstructured":"Xiao J, Jiang H, Zhang R, Fan G, Zhang Y, Jiang D, et al. Augmented cardiac hypertrophy in response to pressure overload in mice lacking ELTD1. PLoS One. 2012;7(5):e35779.","journal-title":"PLoS One"},{"issue":"3","key":"1495_CR58","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1111\/jcmm.12022","volume":"17","author":"C You","year":"2013","unstructured":"You C, Sandalcioglu IE, Dammann P, Felbor U, Sure U, Zhu Y. Loss of CCM3 impairs DLL4-Notch signalling: implication in endothelial angiogenesis and in inherited cerebral cavernous malformations. J Cell Mol Med. 2013;17(3):407\u201318.","journal-title":"J Cell Mol Med"},{"issue":"2","key":"1495_CR59","doi-asserted-by":"publisher","first-page":"570","DOI":"10.1111\/jcmm.17133","volume":"26","author":"M Zalles","year":"2022","unstructured":"Zalles M, Smith N, Saunders D, Lerner M, Fung KM, Battiste J, et al. A tale of two multi-focal therapies for glioblastoma: An antibody targeting ELTD1 and nitrone-based OKN-007. J Cell Mol Med. 2022;26(2):570\u201382.","journal-title":"J Cell Mol Med"},{"issue":"1","key":"1495_CR60","volume":"3","author":"M Zalles","year":"2021","unstructured":"Zalles M, Smith N, Saunders D, Guzman M, Lerner M, Fung KM, et al. ELTD1 as a multi-focal target for malignant gliomas: preclinical studies. Neurooncol Adv. 2021;3(1):vdab132.","journal-title":"Neurooncol Adv"},{"key":"1495_CR61","doi-asserted-by":"crossref","unstructured":"Ziegler J, Pody R, Coutinho de Souza P, Evans B, Saunders D, Smith N, et al. ELTD1, an effective anti-angiogenic target for gliomas: preclinical assessment in mouse GL261 and human G55 xenograft glioma models. Neuro Oncol. 2017;19(2):175\u201385.","DOI":"10.1093\/neuonc\/now147"}],"container-title":["Molecular Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s10020-026-01495-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s10020-026-01495-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s10020-026-01495-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T01:05:24Z","timestamp":1782867924000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s10020-026-01495-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,8]]},"references-count":61,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["1495"],"URL":"https:\/\/doi.org\/10.1186\/s10020-026-01495-4","relation":{},"ISSN":["1528-3658"],"issn-type":[{"value":"1528-3658","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,8]]},"assertion":[{"value":"5 August 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 April 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 May 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"CCM Patients\n                      : The study protocol was strictly performed in accordance with the Declaration of Helsinki and with permission by the local ethical committee of the Hannover Medical School, Germany (Approval Number 6960) and the Ethics Committee of University of Bonn Medical Center (Approval Number 076\/08 and 042\/08). Written informed consent was collected from all the patients involved in this study.\n                      Animal Study\n                      : All experimental animal procedures were conducted in accordance with the ARRIVE guidelines and the European Directive 2010\/63\/EU on the protection of animals used for scientific purposes. The study was approved by the relevant ethics committee and authorized by the French Ministry of Research, and University of Rochester. Animals were housed under standard conditions, and all procedures were performed with attention to minimizing distress and ensuring the well-being of the animals throughout the study.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"98"}}