title: Human brain arteriovenous malformations express lymphatic-associated genes.
abstract: OBJECTIVE
  Brain arteriovenous malformations (AVMs) are devastating, hemorrhage-prone, cerebrovascular lesions characterized by well-defined feeding arteries, draining vein(s) and the absence of a capillary bed. The endothelial cells (ECs) that comprise AVMs exhibit a loss of arterial and venous specification. Given the role of the transcription factor COUP-TFII in vascular development, EC specification, and pathological angiogenesis, we examined human AVM tissue to determine if COUP-FTII may have a role in AVM disease biology.
  
  
  METHODS
  We examined 40 human brain AVMs by immunohistochemistry (IHC) and qRT-PCR for the expression of COUP-TFII as well as other genes involved in venous and lymphatic development, maintenance, and signaling. We also examined proliferation and EC tube formation with human umbilical ECs (HUVEC) following COUP-TFII overexpression.
  
  
  RESULTS
  We report that AVMs expressed COUP-TFII, SOX18, PROX1, NFATC1, FOXC2, TBX1, LYVE1, Podoplanin, and vascular endothelial growth factor (VEGF)-C, contained Ki67-positive cells and heterogeneously expressed genes involved in Hedgehog, Notch, Wnt, and VEGF signaling pathways. Overexpression of COUP-TFII alone in vitro resulted in increased EC proliferation and dilated tubes in an EC tube formation assay in HUVEC.
  
  
  CONCLUSIONS
  This suggests AVM ECs are further losing their arterial/venous specificity and acquiring a partial lymphatic molecular phenotype. There was significant correlation of gene expression with presence of clinical edema and acute hemorrhage. While the precise role of these genes in the formation, stabilization, growth and risk of hemorrhage of AVMs remains unclear, these findings have potentially important implications for patient management and treatment choice, and opens new avenues for future work on AVM disease mechanisms.
authors.affiliation: Department of Neurosurgery, Stanford Neuromolecular Innovation Program, Stanford University 300 Pasteur Drive, Stanford, California, 94305.
authors.forename: Lorelei D
authors.initials: LD
authors.lastname: Shoemaker
authors.affiliation: Department of Neurosurgery, Stanford Neuromolecular Innovation Program, Stanford University 300 Pasteur Drive, Stanford, California, 94305.
authors.forename: Laurel F
authors.initials: LF
authors.lastname: Fuentes
authors.affiliation: Department of Neurosurgery, Stanford Neuromolecular Innovation Program, Stanford University 300 Pasteur Drive, Stanford, California, 94305.
authors.forename: Shauna M
authors.initials: SM
authors.lastname: Santiago
authors.affiliation: Department of Neurosurgery, Stanford Neuromolecular Innovation Program, Stanford University 300 Pasteur Drive, Stanford, California, 94305.
authors.forename: Breanna M
authors.initials: BM
authors.lastname: Allen
authors.affiliation: Centre for Neuroscience Studies and the Department of Surgery, Queen's University Kingston, Ontario, Canada.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Cook
authors.affiliation: Department of Neurosurgery, Stanford Neuromolecular Innovation Program, Stanford University 300 Pasteur Drive, Stanford, California, 94305.
authors.forename: Gary K
authors.initials: GK
authors.lastname: Steinberg
authors.affiliation: Department of Neurosurgery, Stanford Neuromolecular Innovation Program, Stanford University 300 Pasteur Drive, Stanford, California, 94305.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Chang