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Pigment epithelium-derived factor inhibits fibroblast-growth-factor-2-induced capillary morphogenesis of endothelial

Shigeru Kanda1, Yasushi Mochizuki, Takao Nakamura

  • 1Department of Molecular Microbiology and Immunology, Division of Endothelial Cell Biology, Nagasaki University Graduate School of Biomedical Science, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan. shigeruk@net.nagasaki-u.ac.jp

Journal of Cell Science
|February 17, 2005
PubMed

Insights

Pigment epithelium-derived factor (PEDF) inhibits endothelial cell capillary formation by downregulating Fyn kinase activity via Fes. This pathway is crucial for blocking fibroblast growth factor 2 (FGF-2)-induced angiogenesis.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Pigment epithelium-derived factor (PEDF) is known for its anti-angiogenic properties.
  • The precise signal-transduction pathways mediating PEDF's effects are not fully understood.
  • Fibroblast growth factor 2 (FGF-2) promotes angiogenesis, a process involving endothelial cell capillary morphogenesis.

Purpose of the Study:

  • To elucidate the signal-transduction pathways regulated by PEDF in endothelial cells.
  • To investigate the role of Fyn and Fes kinases in PEDF-mediated inhibition of FGF-2-induced capillary morphogenesis.
  • To determine how PEDF affects the activity and interaction of Fyn and Fes.

Main Methods:

  • Using murine brain capillary endothelial cells (IBE cells) and human umbilical-vein endothelial cells (HUVECs).
  • Assessing capillary morphogenesis on growth-factor-reduced Matrigel.
  • Employing kinase inhibitors (PP2), dominant-negative and constitutively active kinase mutants (Fyn, Fes), and analyzing protein colocalization and tyrosine phosphorylation.
  • Utilizing stable cell lines expressing kinase-inactive Fes.

Main Results:

  • PEDF inhibited FGF-2-induced capillary morphogenesis in both IBE cells and HUVECs.
  • PEDF downregulated FGF-2-promoted Fyn activity through C-terminal tyrosine phosphorylation in a Fes-dependent manner.
  • PEDF failed to inhibit capillary morphogenesis or Fyn activity in cells expressing kinase-inactive Fes.
  • Fes was shown to colocalize with Fyn and potentially phosphorylate it, and wild-type Fes enhanced Fyn tyrosine phosphorylation in vitro.
  • Overexpression of active Fyn rendered cells resistant to PEDF treatment.

Conclusions:

  • PEDF inhibits FGF-2-induced endothelial cell capillary morphogenesis.
  • PEDF exerts its inhibitory effect by downregulating Fyn kinase activity through a Fes-dependent mechanism.
  • The Fyn-Fes interaction and Fes-mediated phosphorylation of Fyn are critical for PEDF's anti-angiogenic action in this context.

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