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Platelet-activating factor mediates CD40-dependent angiogenesis and endothelial-smooth muscle cell interaction
Simona Russo1, Benedetta Bussolati, Ilaria Deambrosis
1Dipartimento di Medicina Interna e di Scienze Cliniche e Biologiche, Università di Torino and Centro Ricerca Medicina Sperimentale, Ospedale San Giovanni Battista, Torino, Italy.
Journal of Immunology (Baltimore, Md. : 1950)
|November 11, 2003
Summary
Stimulating CD40 on endothelial cells triggers platelet-activating factor (PAF) synthesis, promoting new blood vessel formation. This pathway is crucial for CD40-induced angiogenesis in inflammatory conditions and tumor growth.
Area of Science:
- Immunology
- Vascular Biology
- Cell Signaling
Background:
- CD40 signaling plays a role in inflammation and vascular processes.
- Platelet-activating factor (PAF) is an inflammatory mediator with angiogenic properties.
Purpose of the Study:
- To investigate if CD40 stimulation induces PAF synthesis in endothelial and smooth muscle cells.
- To determine if PAF contributes to CD40-induced new blood vessel formation (neoangiogenesis).
Main Methods:
- Stimulation of CD40 on cells using soluble CD154 or cell-bound CD154.
- Inhibition studies using a soluble CD40-murine Ig fusion protein and PAF receptor antagonists (WEB2170, CV3988).
- Analysis of intracellular signaling pathways (MAPK pathways) and protein phosphorylation.
- In vitro assays for endothelial cell migration and organization.
- In vivo murine Matrigel plug assay to assess angiogenesis.
Main Results:
- CD40 stimulation induced PAF synthesis in endothelial cells, but not smooth muscle cells.
- PAF synthesis involved phospholipase Cgamma-protein kinase C-Raf-MAPK and MAPK kinase-3/6-p38 MAPK pathways.
- Synthesized PAF promoted endothelial cell migration, vessel-like organization, and endothelial-smooth muscle cell interaction.
- Blocking PAF receptors inhibited CD40-induced angiogenesis in vivo.
Conclusions:
- Endothelial CD40 stimulation triggers PAF synthesis, which is essential for CD40-induced neoangiogenesis.
- This pathway is a potential target for modulating vascular remodeling in inflammatory diseases and cancer.