title: Thrombospondin-1 modulates the angiogenic phenotype of human cerebral arteriovenous malformation endothelial cells.
abstract: BACKGROUND
  The management of cerebral arteriovenous malformation (AVM) is challenging, and invasive therapies place vital intracranial structures at risk of injury. The development of noninvasive, pharmacologic approaches relies on identifying factors that mediate key angiogenic processes. Previous studies indicate that endothelial cells (ECs) derived from cerebral AVM (AVM-ECs) are distinct from control brain ECs with regard to important angiogenic characteristics.
  
  
  OBJECTIVE
  To determine whether thrombospondin-1 (TSP-1), a potent angiostatic factor, regulates critical angiogenic features of AVM-ECs and to identify factors that modulate TSP-1 production in AVM-ECs.
  
  
  METHODS
  EC proliferation, migration, and tubule formation were evaluated with bromodeoxyuridine incorporation, Boyden chamber, and Matrigel studies, respectively. TSP-1 and inhibitor of DNA binding/differentiation 1 (Id1) mRNA levels were quantified with microarray and quantitative real-time polymerase chain reaction analyses. TSP-1 protein expression was measured using Western blotting, immunohistochemical, and enzyme-linked immunosorbent assay techniques. The mechanistic link between Id1 and TSP-1 was established through small interfering RNA-mediated knockdown of Id1 in AVM-ECs followed by Western blot and enzyme-linked immunosorbent assay experiments assessing TSP-1 production.
  
  
  RESULTS
  AVM-ECs proliferate faster, migrate more quickly, and form disorganized tubules compared with brain ECs. TSP-1 is significantly down-regulated in AVM-ECs. The addition of TSP-1 to AVM-EC cultures normalizes the rate of proliferation and migration and the efficiency of tubule formation, whereas brain ECs are unaffected. Id1 negatively regulates TSP-1 expression in AVM-ECs.
  
  
  CONCLUSIONS
  These data highlight a novel role for TSP-1 in the pathobiology of AVM angiogenesis and provide a context for its use in the clinical management of brain AVMs.
authors.affiliation: Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Stapleton
authors.forename: Don L
authors.initials: DL
authors.lastname: Armstrong
authors.forename: Raphael
authors.initials: R
authors.lastname: Zidovetzki
authors.forename: Charles Y
authors.initials: CY
authors.lastname: Liu
authors.forename: Steven L
authors.initials: SL
authors.lastname: Giannotta
authors.forename: Florence M
authors.initials: FM
authors.lastname: Hofman
mesh_terms: D000328:Adult; D042501:Angiogenic Proteins / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D002538:Intracranial Arteriovenous Malformations / Q000235:genetics* / Q000473:pathology* / Q000517:prevention & control; D008297:Male; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000473:pathology* / Q000517:prevention & control; D010641:Phenotype; D019700:Thrombospondin 1 / Q000235:genetics / Q000502:physiology*; D055815:Young Adult
chemical_list: D042501:Angiogenic Proteins; D019700:Thrombospondin 1