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Regulation of VEGF-induced endothelial cell PAF synthesis: role of p42/44 MAPK, p38 MAPK and PI3K pathways

P N Bernatchez1, B G Allen, D S Gélinas

  • 1Research Center, Montreal Heart Institute, Department of Pharmacology, University of Montreal, Montreal, Qc, Canada.

British Journal of Pharmacology
|November 13, 2001
PubMed

Insights

Vascular endothelial growth factor (VEGF) activates endothelial cell (EC) platelet-activating factor (PAF) synthesis via Flk-1 receptor. This involves PLCgamma, PKC, and MAPK pathways, with PI3K acting as a negative regulator.

Area of Science:

  • Cellular and Molecular Biology
  • Endothelial Cell Signaling
  • Inflammation and Angiogenesis Research

Background:

  • Vascular endothelial growth factor (VEGF) is a key mediator of angiogenesis and inflammation.
  • VEGF-induced inflammation involves endothelial cell (EC) platelet-activating factor (PAF) synthesis, requiring Flk-1 receptor activation.
  • The intracellular signaling pathways regulating EC PAF synthesis upon VEGF stimulation are not fully understood.

Purpose of the Study:

  • To elucidate the intracellular signaling cascade involved in VEGF-induced PAF synthesis in endothelial cells.
  • To identify the specific kinases and pathways regulating this process.
  • To investigate the role of the PI3K pathway in modulating VEGF-mediated PAF production.

Main Methods:

  • Utilized specific kinase inhibitors to block signaling pathways.
  • Employed Western blot analysis to assess protein activation.
  • Investigated the effects of VEGF stimulation on bovine aortic endothelial cells (BAEC).

Main Results:

  • VEGF induces PAF synthesis through sequential activation of Flk-1, PLCgamma, PKC, and p42/44 MAPK.
  • p38 MAPK activation is essential for VEGF-mediated conversion of lyso-PAF to PAF.
  • The PI3K pathway is activated by VEGF and negatively regulates EC PAF synthesis, as its blockade potentiates PAF production.

Conclusions:

  • VEGF stimulates EC PAF synthesis via a defined intracellular cascade involving specific MAPK pathways.
  • p38 MAPK plays a critical role in the final conversion step of PAF synthesis.
  • The PI3K pathway acts as a negative feedback mechanism, inhibiting VEGF-induced PAF synthesis in endothelial cells.

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