Complement factor C5a as mast cell activator mediates vascular remodelling in vein graft disease.
OBJECTIVE
Failure of vein graft conduits due to vein graft thickening, accelerated atherosclerosis, and subsequent plaque rupture is applicable to 50% of all vein grafts within 10 years. New potential therapeutic targets to treat vein graft disease may be found in components of the innate immune system, such as mast cells and complement factors, which are known to be involved in atherosclerosis and plaque destabilization. Interestingly, mast cells can be activated by complement factor C5a and, therefore, a direct role for C5a-mediated mast cell activation in vein graft disease is anticipated. We hypothesize that C5a-mediated mast cell activation is involved in the development and destabilization of vein graft lesions.


RESULTS
Mast cells accumulated in time in murine vein graft lesions, and C5a and C5a-receptor (CD88) expression was up-regulated during vein graft disease in apolipoprotein E-deficient mice. Mast cell activation with dinitrophenyl resulted in a profound increase in vein graft thickening and in the number of plaque disruptions. C5a application enhanced vein graft lesion formation, while treatment with a C5a-receptor antagonist resulted in decreased vein graft disease. C5a most likely exerts its function via mast cell activation since the mast cell inhibitor cromolyn totally blocked C5a-enhanced vein graft disease.


CONCLUSIONS
These data provide evidence that complement factor C5a-induced mast cell activation is highly involved in vein graft disease, which identifies new targets to prevent vein graft disease.
Einthoven Laboratory for Experimental Vascular Medicine, Leiden,  The Netherlands.
Margreet R
MR
de Vries
Anouk
A
Wezel
Abbey
A
Schepers
Peter J
PJ
van Santbrink
Trent M
TM
Woodruff
Hans W M
HW
Niessen
Jaap F
JF
Hamming
Johan
J
Kuiper
Ilze
I
Bot
Paul H A
PH
Quax
D000818:Animals; D001057:Apolipoproteins E / Q000502:physiology; D050197:Atherosclerosis / Q000209:etiology; D002478:Cells, Cultured; D015936:Complement C5a / Q000502:physiology*; D016894:Endarterectomy, Carotid; D006801:Humans; D008297:Male; D008407:Mast Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010456:Peptides, Cyclic / Q000494:pharmacology; D014680:Veins / Q000473:pathology / Q000637:transplantation*
D001057:Apolipoproteins E; D010456:Peptides, Cyclic; C504156:hydrocinnamate-cyclo(ornithyl-prolyl-cyclohexylalanyl-tryptophyl-arginyl); D015936:Complement C5a