title: Vascular endothelial growth factor expression in monocytes from patients with primary antiphospholipid syndrome.
abstract: BACKGROUND
  One of the described mechanisms leading to thrombosis in antiphospholipid syndrome (APS) is overexpression of tissue factor (TF) in the monocytes and endothelial cells of patients with antiphospholipid antibodies (aPL). Vascular endothelial growth factor (VEGF) may stimulate monocyte TF expression through its receptor, the tyrosine kinase Flt-1.
  
  
  OBJECTIVE
  This study aimed to analyze the following in monocytes of 55 primary APS patients: VEGF and Flt-1 expression levels, their potential regulation by aPL, and the association of VEGF and Flt-1 expression with the increased TF expression found in APS patients.
  
  
  RESULTS
  Purified monocytes from APS patients showed higher levels of VEGF and Flt-1 than healthy donors, which further correlated with immunoglobulin G (IgG) anticardiolipin titers and TF expression rank. Moreover, monocyte VEGF and Flt-1 levels were significantly higher in patients with than in patients without previous thrombosis. In vitro, IgG from APS patients increased monocyte VEGF and Flt-1 expression in a dose-dependent manner. VEGF and Flt-1 expression was significantly inhibited by the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580; this suggests the involvement of this kinase in the aPL-induced VEGF and Flt-1 upregulation.
  
  
  CONCLUSIONS
  Our data show, for the first time in vivo, that monocytes from primary APS patients have an increased expression of VEGF and Flt-1. Furthermore, in vitro results indicated that this cytokine is produced by monocytes when treated with aPL, and that the p38 MAPK signaling pathway plays an important role. Thus, VEGF might act as a regulatory factor in aPL-mediated monocyte activation and TF expression, thereby contributing to the proinflammatory-prothrombotic phenotype of APS patients.
authors.affiliation: Lupus Research Unit, St Thomas' Hospital, London, UK, and Research Unit and Rheumatology Department, Reina Sofía University Hospital, Cordoba, Spain.
authors.forename: M J
authors.initials: MJ
authors.lastname: Cuadrado
authors.forename: P
authors.initials: P
authors.lastname: Buendía
authors.forename: F
authors.initials: F
authors.lastname: Velasco
authors.forename: M A
authors.initials: MA
authors.lastname: Aguirre
authors.forename: N
authors.initials: N
authors.lastname: Barbarroja
authors.forename: L A
authors.initials: LA
authors.lastname: Torres
authors.forename: M
authors.initials: M
authors.lastname: Khamashta
authors.forename: C
authors.initials: C
authors.lastname: López-Pedrera
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D016736:Antiphospholipid Syndrome / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology; D013925:Thromboplastin / Q000096:biosynthesis*; D013927:Thrombosis / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D042461:Vascular Endothelial Growth Factor A; D013925:Thromboplastin; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580