Discovery and Characterization of Ephrin B2 and EphB4 Dysregulation and Novel Mutations in Cerebral Cavernous Malformations: In Vitro and Patient-Derived Evidence of Ephrin-Mediated Endothelial Cell Pathophysiology

Abengozar MA, de Frutos S, Ferreiro S, Soriano J, Perez-Martinez M, Olmeda D, Marenchino M, Canamero M, Ortega S, Megias D, Rodriguez A, Martinez-Torrecuadrada JL (2012) Blocking ephrinB2 with highly specific antibodies inhibits angiogenesis, lymphangiogenesis, and tumor growth. Blood 119(19):4565–4576. https://doi.org/10.1182/blood-2011-09-380006

Article  CAS  PubMed  Google Scholar 

Akino T, Han X, Nakayama H, McNeish B, Zurakowski D, Mammoto A, Klagsbrun M, Smith E (2014) Netrin-1 promotes medulloblastoma cell invasiveness and angiogenesis, and demonstrates elevated expression in tumor tissue and urine of patients with pediatric medulloblastoma. Can Res 74(14):3716–3726. https://doi.org/10.1158/0008-5472.CAN-13-3116

Article  CAS  Google Scholar 

Aranda E, Owen GI (2009) A semi-quantitative assay to screen for angiogenic compounds and compounds with angiogenic potential using the EA.hy926 endothelial cell line. Biol Res 42(3):377–389

Article  PubMed  Google Scholar 

Chrencik JE, Brooun A, Recht MI, Kraus ML, Koolpe M, Kolatkar AR, Bruce RH, Martiny-Baron G, Widmer H, Pasquale EB, Kuhn P (2006) Structure and thermodynamic characterization of the EphB4/Ephrin-B2 antagonist peptide complex reveals the determinants for receptor specificity. Structure 14(2):321–330. https://doi.org/10.1016/j.str.2005.11.011

Article  CAS  PubMed  Google Scholar 

Duran D, Karschnia P, Gaillard JR, Karimy JK, Youngblood MW, DiLuna ML, Matouk CC, Aagaard-Kienitz B, Smith ER, Orbach DB, Rodesch G, Berenstein A, Gunel M, Kahle KT (2018) Human genetics and molecular mechanisms of vein of Galen malformation. J Neurosurg Pediatr 21(4):367–374. https://doi.org/10.3171/2017.9.PEDS17365

Article  PubMed  Google Scholar 

Duran D, Zeng X, Jin SC, Choi J, Nelson-Williams C, Yatsula B, Gaillard J, Furey CG, Lu Q, Timberlake AT, Dong W, Sorscher MA, Loring E, Klein J, Allocco A, Hunt A, Conine S, Karimy JK, Youngblood MW, Zhang J, DiLuna ML, Matouk CC, Mane S, Tikhonova IR, Castaldi C, Lopez-Giraldez F, Knight J, Haider S, Soban M, Alper SL, Komiyama M, Ducruet AF, Zabramski JM, Dardik A, Walcott BP, Stapleton CJ, Aagaard-Kienitz B, Rodesch G, Jackson E, Smith ER, Orbach DB, Berenstein A, Bilguvar K, Vikkula M, Gunel M, Lifton RP, Kahle KT (2019) Mutations in chromatin modifier and ephrin signaling genes in vein of galen malformation. Neuron 101(3):429-443 e424. https://doi.org/10.1016/j.neuron.2018.11.041

Article  CAS  PubMed  Google Scholar 

Egea J, Klein R (2007) Bidirectional Eph-ephrin signaling during axon guidance. Trends Cell Biol 17(5):230–238. https://doi.org/10.1016/j.tcb.2007.03.004

Article  CAS  PubMed  Google Scholar 

Fehnel KP, Penn DL, Duggins-Warf M, Gruber M, Pineda S, Sesen J, Moses-Gardner A, Shah N, Driscoll J, Zurakowski D, Orbach DB, Smith ER (2020) Dysregulation of the EphrinB2-EphB4 ratio in pediatric cerebral arteriovenous malformations is associated with endothelial cell dysfunction in vitro and functions as a novel noninvasive biomarker in patients. Exp Mol Med 52(4):658–671. https://doi.org/10.1038/s12276-020-0414-0

Article  CAS  PubMed  PubMed Central  Google Scholar 

Gault J, Sarin H, Awadallah NA, Shenkar R, Awad IA (2004) Pathobiology of human cerebrovascular malformations: basic mechanisms and clinical relevance. Neurosurgery 55(1):1–16

Article  PubMed  Google Scholar 

Goss JA, Huang AY, Smith E, Konczyk DJ, Smits PJ, Sudduth CL, Stapleton C, Patel A, Alexandrescu S, Warman ML, Greene AK (2019) Somatic mutations in intracranial arteriovenous malformations. PLoS ONE 14(12):e0226852. https://doi.org/10.1371/journal.pone.0226852

Article  CAS  PubMed  PubMed Central  Google Scholar 

Gross BA, Lin N, Du R, Day AL (2011) The natural history of intracranial cavernous malformations. Neurosurg Focus 30(6):E24

Article  PubMed  Google Scholar 

Guclu B, Ozturk AK, Pricola KL, Bilguvar K, Shin D, O’Roak BJ, Gunel M (2005) Mutations in apoptosis-related gene, PDCD10, cause cerebral cavernous malformation 3. Neurosurgery 57(5):1008–1013

Article  PubMed  Google Scholar 

Haasdijk RA, Cheng C, Maat-Kievit AJ, Duckers HJ (2012) Cerebral cavernous malformations: from molecular pathogenesis to genetic counselling and clinical management. Eur J Hum Genet 20(2):134–140

Article  CAS  PubMed  Google Scholar 

Huang L, Nakayama H, Klagsbrun M, Mulliken JB, Bischoff J (2015) Glucose transporter 1-positive endothelial cells in infantile hemangioma exhibit features of facultative stem cells. Stem Cells 33(1):133–145. https://doi.org/10.1002/stem.1841

Article  CAS  PubMed  Google Scholar 

Kahle KT, Duran D, Smith ER (2023) Increasing precision in the management of pediatric neurosurgical cerebrovascular diseases with molecular genetics. J Neurosurg Pediatr. https://doi.org/10.3171/2022.12.PEDS22332

Article  PubMed  Google Scholar 

Kawasaki J, Aegerter S, Fevurly RD, Mammoto A, Mammoto T, Sahin M, Mably JD, Fishman SJ, Chan J (2014) RASA1 functions in EPHB4 signaling pathway to suppress endothelial mTORC1 activity. J Clin Invest 124(6):2774–2784. https://doi.org/10.1172/JCI67084

Article  CAS  PubMed  PubMed Central  Google Scholar 

Liu J, Dong F, Jeong J, Masuda T, Lobe CG (2014) Constitutively active Notch1 signaling promotes endothelial-mesenchymal transition in a conditional transgenic mouse model. Int J Mol Med 34(3):669–676

Article  CAS  PubMed  PubMed Central  Google Scholar 

Maddaluno L, Rudini N, Cuttano R, Bravi L, Giampietro C, Corada M, Ferrarini L, Orsenigo F, Papa E, Boulday G, Tournier-Lasserve E, Chapon F, Richichi C, Retta SF, Lampugnani MG, Dejana E (2013) EndMT contributes to the onset and progression of cerebral cavernous malformations. Nature 498(7455):492–496. https://doi.org/10.1038/nature12207

Article  CAS  PubMed  Google Scholar 

Peterson K, Coffman S, Zehri A, Anzalone A, Xiang Z, Wolfe S (2021) Somatic mosaicism in the pathogenesis of de novo cerebral arteriovenous malformations: a paradigm shift implicating the RAS-MAPK signaling cascade. Cerebrovasc Dis 50(2):231–238. https://doi.org/10.1159/000512800

Article  PubMed  Google Scholar 

Pricola Fehnel K, Duggins-Warf M, Zurakowski D, McKee-Proctor M, Majumder R, Raber M, Han X, Smith ER (2016) Using urinary bFGF and TIMP3 levels to predict the presence of juvenile pilocytic astrocytoma and establish a distinct biomarker signature. J Neurosurg Pediatr. https://doi.org/10.3171/2015.12.PEDS15448

Article  PubMed  Google Scholar 

Ren AA, Snellings DA, Su YS, Hong CC, Castro M, Tang AT, Detter MR, Hobson N, Girard R, Romanos S, Lightle R, Moore T, Shenkar R, Benavides C, Beaman MM, Muller-Fielitz H, Chen M, Mericko P, Yang J, Sung DC, Lawton MT, Ruppert JM, Schwaninger M, Korbelin J, Potente M, Awad IA, Marchuk DA, Kahn ML (2021) PIK3CA and CCM mutations fuel cavernomas through a cancer-like mechanism. Nature 594(7862):271–276. https://doi.org/10.1038/s41586-021-03562-8

Article  CAS  PubMed  PubMed Central  Google Scholar 

Ren J, Huang Y, Ren Y, Tu T, Qiu B, Ai D, Bi Z, Bai X, Li F, Li JL, Chen XJ, Feng Z, Guo Z, Lei J, Tian A, Cui Z, Lindner V, Adams RH, Wang Y, Zhao F, Korbelin J, Sun W, Wang Y, Zhang H, Hong T, Ge WP (2023) Somatic variants of MAP3K3 are sufficient to cause cerebral and spinal cord cavernous malformations. Brain 146(9):3634–3647. https://doi.org/10.1093/brain/awad104

Article  PubMed  PubMed Central  Google Scholar 

Seker A, Pricola KL, Guclu B, Ozturk AK, Louvi A, Gunel M (2006) CCM2 expression parallels that of CCM1. Stroke 37(2):518–523

Article  CAS  PubMed  Google Scholar 

Snellings DA, Girard R, Lightle R, Srinath A, Romanos S, Li Y, Chen C, Ren AA, Kahn ML, Awad IA, Marchuk DA (2022) Developmental venous anomalies are a genetic primer for cerebral cavernous malformations. Nat Cardiovasc Res 1:246–252. https://doi.org/10.1038/s44161-022-00035-7

Article  PubMed  PubMed Central  Google Scholar 

Takada S, Hojo M, Tanigaki K, Miyamoto S (2017) Contribution of endothelial-to-mesenchymal transition to the pathogenesis of human cerebral and orbital cavernous malformations. Neurosurgery 81(1):176–183. https://doi.org/10.1093/neuros/nyx078

Article  PubMed  Google Scholar 

Tanriover G, Boylan AJ, Diluna ML, Pricola KL, Louvi A, Gunel M (2008) PDCD10, the gene mutated in cerebral cavernous malformation 3, is expressed in the neurovascular unit. Neurosurgery 62(4):930–938

Article  PubMed  Google Scholar 

Van Damme A, Seront E, Dekeuleneer V, Boon LM, Vikkula M (2020) New and emerging targeted therapies for vascular malformations. Am J Clin Dermatol 21(5):657–668. https://doi.org/10.1007/s40257-020-00528-w

Article  PubMed  Google Scholar 

Weng J, Yang Y, Song D, Huo R, Li H, Chen Y, Nam Y, Zhou Q, Jiao Y, Fu W, Yan Z, Wang J, Xu H, Di L, Li J, Wang S, Zhao J, Wang J, Cao Y (2021) Somatic MAP3K3 mutation defines a subclass of cerebral cavernous malformation. Am J Hum Genet 108(5):942–950. https://doi.org/10.1016/j.ajhg.2021.04.005

Article  CAS  PubMed  PubMed Central  Google Scholar 

You C, Zhao K, Dammann P, Keyvani K, Kreitschmann-Andermahr I, Sure U, Zhu Y (2017) EphB4 forward signalling mediates angiogenesis caused by CCM3/PDCD10-ablation. J Cell Mol Med 21(9):1848–1858. https://doi.org/10.1111/jcmm.13105

Article  CAS  PubMed  PubMed Central  Google Scholar 

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