title: Splice variants of tissue factor promote monocyte-endothelial interactions by triggering the expression of cell adhesion molecules via integrin-mediated signaling.
abstract: BACKGROUND
  TF is highly expressed in cancerous and atherosclerotic lesions. Monocyte recruitment is a hallmark of disease progression in these pathological states.
  
  
  OBJECTIVE
  To examine the role of integrin signaling in TF-dependent recruitment of monocytes by endothelial cells.
  
  
  METHODS
  The expression of flTF and asTF in cervical cancer and atherosclerotic lesions was examined. Biologic effects of the exposure of primary microvascular endothelial cells (MVEC) to truncated flTF ectodomain (LZ-TF) and recombinant asTF were assessed.
  
  
  RESULTS
  flTF and asTF exhibited nearly identical expression patterns in cancer lesions and lipid-rich plaques. Tumor lesions, as well as stromal CD68(+)  monocytes/macrophages, expressed both TF forms. Primary MVEC rapidly adhered to asTF and LZ-TF, and this was completely blocked by anti-β1 integrin antibody. asTF- and LZ-TF-treatment of MVEC promoted adhesion of peripheral blood mononuclear cells (PBMCs) under orbital shear conditions and under laminar flow; asTF-elicited adhesion was more pronounced than that elicited by LZ-TF. Expression profiling and western blotting revealed a broad activation of cell adhesion molecules (CAMs) in MVEC following asTF treatment including E-selectin, ICAM-1 and VCAM-1. In transwell assays, asTF potentiated PMBC migration through MVEC monolayers by ∼3-fold under MCP-1 gradient.
  
  
  CONCLUSIONS
  TF splice variants ligate β1 integrins on MVEC, which induces the expression of CAMs in MVEC and leads to monocyte adhesion and transendothelial migration. asTF appears more potent than flTF in eliciting these effects. Our findings underscore the pathophysiologic significance of non-proteolytic, integrin-mediated signaling by the two naturally occurring TF variants in cancer and atherosclerosis.
authors.affiliation: Division of Hematology/Oncology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: R
authors.initials: R
authors.lastname: Srinivasan
authors.forename: E
authors.initials: E
authors.lastname: Ozhegov
authors.forename: Y W
authors.initials: YW
authors.lastname: van den Berg
authors.forename: B J
authors.initials: BJ
authors.lastname: Aronow
authors.forename: R S
authors.initials: RS
authors.lastname: Franco
authors.forename: M B
authors.initials: MB
authors.lastname: Palascak
authors.forename: J T
authors.initials: JT
authors.lastname: Fallon
authors.forename: W
authors.initials: W
authors.lastname: Ruf
authors.forename: H H
authors.initials: HH
authors.lastname: Versteeg
authors.forename: V Y
authors.initials: VY
authors.lastname: Bogdanov
mesh_terms: D017398:Alternative Splicing; D015153:Blotting, Western; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology*; D005260:Female; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013925:Thromboplastin / Q000235:genetics*; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000473:pathology
chemical_list: D015815:Cell Adhesion Molecules; D016023:Integrins; D013925:Thromboplastin