title: Angiopoietin-1 and vascular endothelial growth factor regulation of leukocyte adhesion to endothelial cells: role of nuclear receptor-77.
abstract: OBJECTIVE
  Vascular endothelial growth factor (VEGF) promotes leukocyte adhesion to endothelial cells (ECs). Angiopoietin-1 (Ang-1) inhibits this response. Nuclear receptor-77 (Nur77) is a proangiogenic nuclear receptor. In the present study, we assessed the influence of Ang-1 and VEGF on Nur77 expression in ECs, and evaluated its role in Ang-1/VEGF-mediated leukocyte adhesion.
  
  
  RESULTS
  Expression of Nur77 was evaluated with real-time polymerase chain reaction and immunoblotting. Adhesion of leukocytes to ECs was monitored with inverted microscopy. Nur77 expression or activity was inhibited using adenoviruses expressing dominant-negative form of Nur77, retroviruses expressing Nur77 in the antisense direction, and small interfering RNA oligos. Both Ang-1 and VEGF induce Nur77 expression, by >5- and 30-fold, respectively. When combined, Ang-1 potentiates VEGF-induced Nur77 expression. Ang-1 induces Nur77 through the phosphoinositide 3-kinase and extracellular signal-regulated protein kinase 1/2 pathways. VEGF induces Nur77 expression through the protein kinase D/histone deacetylase 7/myocyte enhancer factor 2 and extracellular signal-regulated protein kinase 1/2 pathways. VEGF induces nuclear factor-kappaB transcription factor, vascular cell adhesion molecule-1, and E-selectin expressions, and promotes leukocyte adhesion to ECs. Ang-1 inhibits these responses. This inhibitory effect of Ang-1 disappears when Nur77 expression is disrupted, restoring the inductive effects of VEGF on adhesion molecule expression, and increased leukocyte adhesion to ECs.
  
  
  CONCLUSIONS
  Nur77 promotes anti-inflammatory effects of Ang-1, and functions as a negative feedback inhibitor of VEGF-induced EC activation.
authors.affiliation: Critical Care and Respiratory Divisions, Department of Medicine, McGill University Health Centre and Meakins-Christie Laboratories, McGill University, Montréal, Québec, Canada.
authors.forename: Hodan
authors.initials: H
authors.lastname: Ismail
authors.forename: Mahroo
authors.initials: M
authors.lastname: Mofarrahi
authors.forename: Raquel
authors.initials: R
authors.lastname: Echavarria
authors.forename: Sharon
authors.initials: S
authors.lastname: Harel
authors.forename: Eric
authors.initials: E
authors.lastname: Verdin
authors.forename: Hyung W
authors.initials: HW
authors.lastname: Lim
authors.forename: Zheng-Gen
authors.initials: ZG
authors.lastname: Jin
authors.forename: Jianxin
authors.initials: J
authors.lastname: Sun
authors.forename: Huiyan
authors.initials: H
authors.lastname: Zeng
authors.forename: Sabah N A
authors.initials: SN
authors.lastname: Hussain
mesh_terms: D042683:Angiopoietin-1 / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics; D007962:Leukocytes / Q000187:drug effects* / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D050396:TRPP Cation Channels / Q000378:metabolism; D020298:U937 Cells; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*
chemical_list: D042683:Angiopoietin-1; D006655:Histone Deacetylases; D051550:I-kappa B Kinase; D016328:NF-kappa B; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D050396:TRPP Cation Channels; D019010:Vascular Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; C539821:NR4A1 protein, human; C543273:HDAC7 protein, human