title: Contribution of Endothelial-to-Mesenchymal Transition to the Pathogenesis of Human Cerebral and Orbital Cavernous Malformations.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  To elucidate the contribution of EndMT, the Notch pathway, and ephrin-B2/EphB4 signaling to the pathogenesis of human intracranial CMs.
  
  
  METHODS
  Eight human intracranial CMs (5 cerebral and 3 orbital CMs) were immunohistochemically investigated.
  
  
  RESULTS
  CD31 (an endothelial marker) and EndMT markers, such as α-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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.|Research Institute, Shiga Medical Center, Shiga, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Takada
authors.affiliation: Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.|Department of Neurosurgery, Shiga Medical Center for Adults, Shiga, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Hojo
authors.affiliation: Research Institute, Shiga Medical Center, Shiga, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Tanigaki
authors.affiliation: Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Miyamoto
mesh_terms: D000199:Actins / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D016543:Central Nervous System Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D002648:Child; D042783:Endothelial Cells / Q000502:physiology*; D036388:Ephrin-B2 / Q000378:metabolism; D005260:Female; D020786:Hemangioma, Cavernous, Central Nervous System / Q000209:etiology* / Q000473:pathology*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009918:Orbital Neoplasms / Q000209:etiology* / Q000473:pathology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D036224:Receptor, EphB4 / Q000378:metabolism; D000071656:Receptor, Notch3 / Q000378:metabolism; D015398:Signal Transduction; D055815:Young Adult
chemical_list: D000199:Actins; D015415:Biomarkers; C497483:CD44 protein, human; D036388:Ephrin-B2; D018960:Hyaluronan Receptors; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D000071656:Receptor, Notch3; D036224:Receptor, EphB4
keywords: Cavernous malformation; Endothelial-to-mesenchymal transition (EndMT); Ephrin-B2/EphB4; Notch signaling