title: TWEAK is an endothelial cell growth and chemotactic factor that also potentiates FGF-2 and VEGF-A mitogenic activity.
abstract: OBJECTIVE
  TWEAK, a member of the tumor necrosis factor superfamily, binds to the Fn14 receptor and stimulates angiogenesis in vivo. In this study, we investigated Fn14 gene expression in human endothelial cells (ECs) and examined the effect of TWEAK, added either alone or in combination with fibroblast growth factor-2 (FGF-2) or vascular endothelial growth factor-A (VEGF-A), on EC proliferation, migration, and survival in vitro. We also determined whether a soluble Fn14-Fc fusion protein could inhibit TWEAK biologic activity on ECs and investigated TWEAK signal transduction in ECs.
  
  
  RESULTS
  We found that both FGF-2 and VEGF-A could induce Fn14 mRNA expression in ECs. TWEAK was a mitogen for ECs, and this proliferative activity could be inhibited by an Fn14-Fc decoy receptor. Furthermore, TWEAK treatment activated several intracellular signaling pathways in ECs and potentiated FGF-2--and VEGF-A--stimulated EC proliferation. TWEAK also had EC chemotactic activity, but it did not promote EC survival.
  
  
  CONCLUSIONS
  These results indicate that TWEAK is an EC growth and migration factor but not a survival factor. TWEAK can also enhance both FGF-2 and VEGF-A mitogenic activity on ECs. Thus, TWEAK may act alone as well as in combination with FGF-2 or VEGF-A to regulate pathological angiogenesis.
authors.affiliation: Department of Vascular Biology, Jerome H Holland Laboratory for the Biomedical Sciences, American Red Cross, 15601 Crabbs Branch Way, Rockville, Md 20855, USA.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Donohue
authors.forename: Christine M
authors.initials: CM
authors.lastname: Richards
authors.forename: Sharron A N
authors.initials: SA
authors.lastname: Brown
authors.forename: Heather N
authors.initials: HN
authors.lastname: Hanscom
authors.forename: John
authors.initials: J
authors.lastname: Buschman
authors.forename: Shobha
authors.initials: S
authors.lastname: Thangada
authors.forename: Timothy
authors.initials: T
authors.lastname: Hla
authors.forename: Mark S
authors.initials: MS
authors.lastname: Williams
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Winkles
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000494:pharmacology* / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D002630:Chemotactic Factors / Q000494:pharmacology*; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D000074049:Cytokine TWEAK; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000494:pharmacology; D007074:Immunoglobulin G / Q000494:pharmacology; D051379:Mice; D008934:Mitogens / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
chemical_list: D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D002630:Chemotactic Factors; D016895:Culture Media, Serum-Free; D000074049:Cytokine TWEAK; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D008934:Mitogens; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; C000613297:TNFRSF12A protein, human; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; C491645:Tnfsf12 protein, mouse; D048069:Tumor Necrosis Factors; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2