Fibulin-5 antagonizes vascular endothelial growth factor (VEGF) signaling and angiogenic sprouting by endothelial cells

DNA Cell Biol. 2004 Jun;23(6):367-79. doi: 10.1089/104454904323145254.


Fibulin-5 (FBLN-5) is a widely expressed, integrin-binding extracellular matrix protein that mediates endothelial cell adhesion and scaffolds cells to elastic fibers. It is also a gene target of TGF-beta in fibroblasts and endothelial cells that regulates cell proliferation and motility in a context-specific manner. Whereas FBLN-5 expression is low in adult vasculature, its expression is high in developing and injured vasculature, implicating FBLN-5 in regulating angiogenesis and endothelial cell function. We show here that TGF-beta stimulates FBLN-5 expression in endothelial cells, and that this response was inhibited by coadministration of the proangiogenic factor, VEGF. FBLN-5 expression was downregulated significantly during endothelial cell tubulogenesis, implying that FBLN-5 expression antagonizes angiogenesis. Accordingly, FBLN-5 overexpression in or recombinant FBLN-5 treatment of endothelial cells abrogated their ability to undergo angiogenic sprouting, doing so by inhibiting endothelial cell proliferation and invasion through Matrigel matrices. Moreover, FBLN-5 antagonized VEGF signaling in endothelial cells, as well as enhanced their expression of the antiangiogenic factor, thrombospondin-1. Finally, the ability of FBLN-5 to antagonize angiogenic processes was determined to be independent of its integrin-binding RGD motif. Collectively, our findings establish FBLN-5 as a novel antagonist of angiogenesis and endothelial cell activities, and offer new insights into why tumorigenesis downregulates FBLN-5 expression.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Angiogenesis Inhibitors / metabolism*
  • Animals
  • Baculoviridae
  • Blotting, Northern
  • DNA Primers
  • DNA, Complementary / genetics
  • Endothelial Cells
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism*
  • Gene Expression Regulation
  • Genetic Vectors
  • Humans
  • Luciferases / metabolism
  • Mice
  • Mutagenesis, Site-Directed
  • Neovascularization, Physiologic / physiology*
  • Plasmids / genetics
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism*
  • Sequence Analysis, DNA
  • Signal Transduction*
  • Thrombospondin 1 / metabolism
  • Transforming Growth Factor beta / metabolism*
  • Tritium
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor A / metabolism


  • Angiogenesis Inhibitors
  • DNA Primers
  • DNA, Complementary
  • Extracellular Matrix Proteins
  • FBLN5 protein, human
  • Fbln5 protein, mouse
  • Recombinant Proteins
  • Thrombospondin 1
  • Transforming Growth Factor beta
  • Vascular Endothelial Growth Factor A
  • Tritium
  • Luciferases