{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T16:58:28Z","timestamp":1792515508701,"version":"4.5.0"},"reference-count":40,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["NEUROSURGERY","NEUROS"],"published-print":{"date-parts":[[2017,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    <jats:bold>BACKGROUND:<\/jats:bold>\n                    The analysis of gene-targeted mouse mutants has demonstrated that endothelial-to-mesenchymal transition (EndMT) is crucial to the onset and progression of cerebral cavernous malformations (CMs). It has also been shown that Notch and ephrin\/Eph signaling are involved in EndMT. However, their roles in the pathogenesis of human intracranial CMs remain unclear.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>OBJECTIVE:<\/jats:bold>\n                    To elucidate the contribution of EndMT, the Notch pathway, and ephrin-B2\/EphB4 signaling to the pathogenesis of human intracranial CMs.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>METHODS:<\/jats:bold>\n                    Eight human intracranial CMs (5 cerebral and 3 orbital CMs) were immunohistochemically investigated.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>RESULTS:<\/jats:bold>\n                    CD31 (an endothelial marker) and EndMT markers, such as \u03b1-smooth muscle actin (a mesenchymal marker) and CD44 (a mesenchymal stem cell marker), were expressed in the endothelial layer of vascular sinusoids in all cases, suggesting that endothelial cells (ECs) have acquired mesenchymal and stem-cell-like characteristics and undergone EndMT in all cerebral and orbital CMs. EndMT was observed in about 70% and 35% of ECs in cerebral and orbital CMs, respectively. In all cases, Notch3 was expressed in the endothelial layer, indicating that ECs of vascular sinusoids have acquired mesenchymal features. In all cases, both ephrin-B2 and EphB4 were detected in the endothelial layer, suggesting that ECs of vascular sinusoids are immature or malformed cells and have both arterial and venous characteristics.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>CONCLUSION:<\/jats:bold>\n                    EndMT plays a critical role in the pathogenesis of human cerebral and orbital CMs. Modulating EndMT is expected to be a new therapeutic strategy for cerebral and orbital CMs.\n                  <\/jats:p>","DOI":"10.1093\/neuros\/nyx078","type":"journal-article","created":{"date-parts":[[2017,2,15]],"date-time":"2017-02-15T03:57:32Z","timestamp":1487131052000},"page":"176-183","source":"Crossref","is-referenced-by-count":28,"title":["Contribution of Endothelial-to-Mesenchymal Transition to the Pathogenesis of Human Cerebral and Orbital Cavernous Malformations"],"prefix":"10.1227","volume":"81","author":[{"given":"Shigeki","family":"Takada","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Japan"},{"name":"Research Institute, Shiga Medical Center, Shiga, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masato","family":"Hojo","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Japan"},{"name":"Department of Neurosurgery, Shiga Medical Center for Adults, Shiga, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenji","family":"Tanigaki","sequence":"additional","affiliation":[{"name":"Research Institute, Shiga Medical Center, Shiga, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susumu","family":"Miyamoto","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2017,7]]},"reference":[{"issue":"(3)","key":"bib1-20231011","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"},{"issue":"(7455)","key":"bib2-20231011","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1038\/nature12207","article-title":"EndMT contributes to the onset and progression of cerebral cavernous malformations","volume":"498","author":"Maddaluno","year":"2013","journal-title":"Nature"},{"issue":"(9)","key":"bib3-20231011","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1002\/iub.1059","article-title":"The role of endothelial-mesenchymal transition in development and pathological process","volume":"64","author":"Lin","year":"2012","journal-title":"IUBMB Life"},{"issue":"(5)","key":"bib4-20231011","doi-asserted-by":"crossref","first-page":"702","DOI":"10.3171\/jns.1991.75.5.0702","article-title":"An analysis of the natural history of cavernous angiomas","volume":"75","author":"Del Curling","year":"1991","journal-title":"J Neurosurg"},{"issue":"(6)","key":"bib5-20231011","doi-asserted-by":"crossref","first-page":"E24","DOI":"10.3171\/2011.3.FOCUS1165","article-title":"The natural history of intracranial cavernous malformations","volume":"30","author":"Gross","year":"2011","journal-title":"Neurosurg Focus"},{"issue":"(1)","key":"bib6-20231011","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/S0090-3019(96)00425-9","article-title":"An analysis of the natural history of cavernous malformations","volume":"48","author":"Kim","year":"1997","journal-title":"Surg Neurol"},{"issue":"(5)","key":"bib7-20231011","doi-asserted-by":"crossref","first-page":"709","DOI":"10.3171\/jns.1991.75.5.0709","article-title":"Natural history of the cavernous angioma","volume":"75","author":"Robinson","year":"1991","journal-title":"J Neurosurg"},{"issue":"(9144)","key":"bib8-20231011","doi-asserted-by":"crossref","first-page":"1892","DOI":"10.1016\/S0140-6736(98)03011-6","article-title":"Hereditary cerebral cavernous angiomas: clinical and genetic features in 57 French families","volume":"352","author":"Labauge","year":"1998","journal-title":"Lancet"},{"issue":"(6)","key":"bib9-20231011","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1056\/NEJM198808113190605","article-title":"Cerebral cavernous malformations. 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