CD40 ligand inhibits endothelial cell migration by increasing production of endothelial reactive oxygen species.
BACKGROUND
The CD40/CD40 ligand system is involved in atherogenesis. Activated T lymphocytes and platelets, which express high amounts of CD40 ligand (CD40L) on their surface, contribute significantly to plaque instability with ensuing thrombus formation, leading to acute coronary syndromes. Because reendothelialization may play a pivotal role for plaque stabilization, we investigated a potential role of CD40L on endothelial cell (EC) migration.


RESULTS
Stimulation of ECs with recombinant CD40L prevented vascular endothelial growth factor (VEGF)-induced EC migration, as determined by a "scratched wound assay." In addition, activated T lymphocytes and platelets significantly inhibited VEGF-induced EC migration and tube formation in vitro. Because the activation of endothelial nitric oxide (NO) synthase and the release of NO are required for EC migration and angiogenesis, we analyzed the effect of NO. Coincubation with the NO donor S-nitroso-N-acetyl-penicillamine (SNAP) did not reverse the inhibitory effect of CD40L on VEGF-induced EC migration and tube formation. In addition, EC migration induced by SNAP was completely inhibited by CD40L. CD40L, however, induced the production of reactive oxygen species and reduced endothelial NO bioavailability. This reactive oxygen species-dependent effect of CD40L stimulation was reversed with vitamin C or N-acetylcysteine.


CONCLUSIONS
The activation of the CD40 receptor inhibits EC migration by increasing reactive oxygen species. The blockade of EC migration by CD40L may critically affect endothelial regeneration after plaque erosion and thereby may contribute to the increased risk for development of acute coronary events in patients with high circulating levels of CD40L.
Urbich
Carmen
C
Molecular Cardiology, Department of Internal Medicine IV, University of Frankfurt, Frankfurt, Germany.
Dernbach
Elisabeth
E
Aicher
Alexandra
A
Zeiher
Andreas M
AM
Dimmeler
Stefanie
S
D000975:Antioxidants / Q000494:pharmacology; D001792:Blood Platelets / Q000502:physiology; D023201:CD40 Ligand / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors; D004730:Endothelium, Vascular / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism* / Q000502:physiology*; D006801:Humans; D008213:Lymphocyte Activation; D008222:Lymphokines / Q000037:antagonists & inhibitors; D009569:Nitric Oxide / Q000096:biosynthesis; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000975:Antioxidants; D016228:Endothelial Growth Factors; D008222:Lymphokines; D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D023201:CD40 Ligand; D009569:Nitric Oxide